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Dietary Intake and Cholelithiasis: A Review. Kotrotsios Anastasios,Tasis Nikolaos,Angelis Stavros,Apostolopoulos Alexandros P,Vlasis Konstantinos,Papadopoulos Vasilios,Filippou Dimitrios K Journal of long-term effects of medical implants Gallbladder disease (GBD) is one of the most prevalent gastrointestinal disorders in western societies. Etiology is multifactorial and may follow complex interaction between genetic and environmental factors. Dietary intake has been considered as a potentially modifiable risk factor for GBD, because a number of dietary factors have been involved in cholelithiasis pathogenesis. In our aim to evaluate potential usefulness of diet pattern modification for GBD prevention, we perform a systematic review of related epidemiological studies. We define GBD as a disorder in which a patient bears gallstones and/or undergoes surgery for gallstones. We review English-language studies found in the Med-line database that occurred from 1973 to 2018. We searched for epidemiological evidence of the role of diet as a potential risk factor for gallstone formation. In particular, we thoroughly inspected intake of fatty acid, cholesterol, carbohydrate, protein, fiber, alcohol, nuts, and coffee and vegetarian eating-pattern effects. Our results show that simple sugar (simple carbohydrate) and saturated fat consumption suggests a positive association with the risk for gallstone formation. Protein, fiber, nuts, coffee, and moderate alcohol intake consistently reduces that probability. Different studies found that fat and cholesterol intake are variable risk factors for GBD; therefore, additional analyses are necessary to clarify their relevance in gallstone formation pathogenesis. GBD is a multifactorial disorder that can be affected both positively and negatively by diet. Although no specific dietary recommendations can be addressed to reduce risk for gallstone formation, healthy diet patterns can be expected to improve prospects for healthy gallbladder function. 10.1615/JLongTermEffMedImplants.2020034732
Genetically Predicted Circulating Copper and Risk of Chronic Kidney Disease: A Mendelian Randomization Study. Ahmad Shafqat,Ärnlöv Johan,Larsson Susanna C Nutrients Elevated circulating copper levels have been associated with chronic kidney disease (CKD), kidney damage, and decline in kidney function. Using a two sample Mendelian randomization approach where copper-associated genetic variants were used as instrumental variables, genetically predicted higher circulating copper levels were associated with higher CKD prevalence (odds ratio 1.17; 95% confidence interval 1.04, 1.32; -value = 0.009). There was suggestive evidence that genetically predicted higher copper was associated with a lower estimated glomerular filtration rate and a more rapid kidney damage decline. In conclusion, we observed that elevated circulating copper levels may be a causal risk factor for CKD. 10.3390/nu14030509
Investigating Causal Relations between Genetic-Related Intermediate Endophenotype and Risk of Chronic Prostatitis: Mendelian Randomization Study. Oxidative medicine and cellular longevity Objective:Prostatitis is a common disease of the male genitourinary system, which seriously disturbs the physical and mental health of male patients. It is related to many factors such as living habits, age, and race, but the etiology has not been fully elucidated. This study investigated whether there is a causal relationship between clinical biochemical indicators (i.e., intermediate phenotype) and prostatitis through Mendelian randomization. The subjects of the study were prostatitis patients and related SNPs in the Guangxi Fangchenggang health examination cohort. Methods:According to the requirements of Mendelian randomization (MR), the single nucleotide polymorphisms (SNPs) related to prostatitis patients and 29 common SNPs related to clinical biochemical indicators were analyzed by linkage disequilibrium, and the calculated SNPs were selected. Finally, the related SNPs were analyzed by Mendelian randomization method. Results:15 biochemical indicators such as complement C4, FOL, CRP, HCY, and estradiol have shared chronic prostatitis SNP sites, and five qualified SNPs were finally screened for complement C4. Finally, complement C4 was obtained by Mendelian randomization method ( = 0.039), which was statistically significant. The other 28 clinical endophenotypes were all negative. Conclusion:The results show that there was a causal relationship between complement C4 and prostatitis, and the more consistent SNP is rs2075799. 10.1155/2022/4560609
Causal Effects of Circulating Cytokines on the Risk of Psoriasis Vulgaris: A Mendelian Randomization Study. Frontiers in genetics Psoriasis vulgaris is an inflammatory skin disease. Observational studies have shown associations between circulating cytokine levels and psoriasis vulgaris. But the causal relationship between circulating cytokine and psoriasis vulgaris remains elusive. To assess the causal effects of cytokine levels on the risk of psoriasis vulgaris and vice versa, we performed a two-sample Mendelian randomization (MR) study by using the inverse-variance weighted (IVW), weighted median, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) in genome-wide association summary statistics of 41 circulating cytokines in up to 8,293 individuals and psoriasis vulgaris in 399,883 individuals. We identified that increasing RANTES level induced an elevated risk of psoriasis vulgaris in IVW ( = 0.33, S.E. = 0.12, = 0.006). This causal effect showed consistency across the weighted median ( = 0.35, S.E. = 0.15, = 0.022) and MR-PRESSO method ( = 0.33, S.E. = 0.11, = 0.028). Our results suggest a potential causal effect of elevated RANTES concentration on the increased risk of psoriasis vulgaris. 10.3389/fgene.2022.941961
Correction to: Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study. Arteriosclerosis, thrombosis, and vascular biology 10.1161/ATV.0000000000000095
Cannabis use and the risk of periodontitis: A two-sample Mendelian randomization study. Journal of clinical periodontology AIM:This study aimed to leverage human genetic data to investigate whether cannabis use causally affects periodontitis. MATERIALS AND METHODS:Data were obtained from summary statistics of genome-wide association studies of lifetime cannabis use (N = 184,765), cannabis use disorder (17,068 cases; 357,219 controls), and periodontitis (17,353 cases; 28,210 controls). We performed two-sample Mendelian randomization (MR) analysis using 6 genetic variants as instrumental variables for lifetime cannabis use and 11 variants as instruments for cannabis use disorder to estimate associations with periodontitis. RESULTS:There was no evidence for an association between genetic liability for lifetime cannabis use or cannabis use disorder with periodontitis. The estimates from the primary analyses were supported in multivariable MR analysis, which considered potential pleiotropic pathways and in weak instrument analyses. CONCLUSIONS:This study provides little evidence to support a detrimental effect of genetic liability for cannabis use on periodontal health. 10.1111/jcpe.13632
Circulating serum vitamin D levels and total body bone mineral density: A Mendelian randomization study. Sun Jing-Yi,Zhao Ming,Hou Yajun,Zhang Cheng,Oh Jinrok,Sun Zheng,Sun Bao-Liang Journal of cellular and molecular medicine Until recently, randomized controlled trials have not demonstrated convincing evidence that vitamin D, or vitamin D in combination with calcium supplementation could improve bone mineral density (BMD), osteoporosis and fracture. It remains unclear whether vitamin D levels are causally associated with total body BMD. Here, we performed a Mendelian randomization study to investigate the association of vitamin D levels with total body BMD using a large-scale vitamin D genome-wide association study (GWAS) dataset (including 79 366 individuals) and a large-scale total body BMD GWAS dataset (including 66,628 individuals). We selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. All these three methods did not show statistically significant association of genetically increased vitamin D levels with total body BMD. Importantly, our findings are consistent with recent randomized clinical trials and Mendelian randomization study. In summary, we provide genetic evidence that increased vitamin D levels could not improve BMD in the general population. Hence, vitamin D supplementation alone may not be associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. 10.1111/jcmm.14153
Educational attainment could be a protective factor against obstructive sleep apnea: a study based on Mendelian randomization. Journal of thoracic disease BACKGROUND:Causality between education and obstructive sleep apnea (OSA) is not known. METHODS:Genetic variants, as instrumental variables for years of education, were derived from the Social Science Genetic Association Consortium. The outcome datasets related to OSA were from the FinnGen research project (www.finngen.fi/en/). Inverse variance-weighted, weighted-median, and Mendelian randomization-Egger analysis were used to estimate causal effects. To assess the robustness and horizontal pleiotropy of significant results, leave-one-out sensitivity analysis and Mendelian randomization-Egger regression analysis were conducted. The inverse variance-weighted method was undertaken to estimate the association between years of education and other known risk factors for OSA. Analyses were conducted using the Two Sample Mendelian Randomization package of R 4·0·3. RESULTS:Genetic predisposition towards 4.2 years of additional education was associated with a 27.8% lower risk of OSA [odds ratio (OR) =0.722, 95% confidence interval (CI): 0.566-0.921; P=0.009]. Sensitivity analyses were consistent with a causal interpretation in which a major bias from genetic pleiotropy was unlikely. The Mendelian randomization assumptions did not seem to be violated. Genetic predisposition towards longer education was associated with a lower body mass index, fewer cigarettes smoked per day, and greater alcohol intake per week. CONCLUSIONS:Our data indicated that education could be a protective factor against OSA. Potential mechanisms could include body mass index, tobacco smoking, and alcohol intake. 10.21037/jtd-21-945
Causal link between lipid profile and bone mineral density: A Mendelian randomization study. Yang Xiao-Lin,Cui Zhi-Zhen,Zhang Hong,Wei Xin-Tong,Feng Gui-Juan,Liu Lu,Liu Yao-Zhong,Pei Yu-Fang,Zhang Lei Bone The level of serum lipids is associated with bone mineral density (BMD), an important skeletal trait. Yet the causality has not been determined. Here we performed a Mendelian randomization (MR) analysis to test potential causal links between BMD and lipid profile, i.e., low-density lipoprotein cholesterol (LDC-c), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c). We observed causal effect of LDL-c, TC and TG to BMD, and reversely the effect of BMD to HDL-c. We further explored the effect of body mass index (BMI) in these causalities and found that the effect of LDL-c, TC and TG to BMD is independent of BMI. Our findings provided useful information in the clinical relevance of blood lipids on BMD variation and osteoporosis risk. 10.1016/j.bone.2019.05.037
Plasma Phospholipid Fatty Acids and Risk of Atrial Fibrillation: A Mendelian Randomization Study. Yuan Shuai,Larsson Susanna C Nutrients Available evidence on the associations of dietary and circulating levels of long-chain n-3 fatty acids, which have potential antiarrhythmic properties, and other fatty acids with atrial fibrillation is conflicting and limited. We conducted a Mendelian randomization study to assess the associations between plasma phospholipid fatty acid levels and atrial fibrillation. Summary-level data of atrial fibrillation were available from 65,446 cases and 522,744 non-cases included in the Atrial Fibrillation Consortium. Sixteen single-nucleotide polymorphisms associated with ten fatty acids at significance level of < 5 × 10 were identified as instrumental variables from the hitherto largest genome-wide association studies for plasma fatty acids. The fixed-effects inverse-variance weighted method was used to assess the association of individual plasma fatty acids and atrial fibrillation risk. The random-effects inverse-variance weighted method, weighted median method, and Mendelian randomization (MR)-Egger method were employed as the sensitivity analyses. Genetic predisposition to higher levels of any of the ten individual fatty acids was not associated with atrial fibrillation risk. 10.3390/nu11071651
Vitamin C and the risk of atrial fibrillation: Mendelian randomization study may be misleading. Clinical nutrition (Edinburgh, Scotland) 10.1016/j.clnu.2022.04.029
Fat mass and fat-free mass in relation to cardiometabolic diseases: a two-sample Mendelian randomization study. Larsson S C,Burgess S Journal of internal medicine 10.1111/joim.13078
Investigating the causal relationship between neuroticism and depression via Mendelian randomization. Speed D,Hemani G,Speed M S, ,Børglum A D,Østergaard S D Acta psychiatrica Scandinavica 10.1111/acps.13009
[Mendelian randomization study of the relationship between high-density lipoprotein cholesterol and age-related macular degeneration]. Qin Xue-ying,Tian Jun,Fang Kai,Li Juan,Yu Wen-zhen,Hou Jing,Chen Da-fang,Li Xiao-xin,Hu Yong-hua Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences OBJECTIVE:To explore genetic variants robustly associated with high-density lipoprotein cholesterol (HDL-C) by Mendelian randomization analysis and to examine its causal association with age-related macular degeneration (AMD). METHODS:AMD cases and controls were selected from several hospitals nationwide. Their AMD was diagnosed by eye examination, serum HDL-C levels were examined by blood tests, and other informations were also collected including demographic characteristics, high risk behaviors and so on. The genetic loci hepatic lipase gene (LIPC) rs10468017 was used as instrumental variables for HDL-C. RESULTS:The study population contained hospital-based 545 AMD patients and 480 controls. The LIPC genotypes were unrelated to all potentially confounding factors measured in this study. In conventional multivariable analyses, the HDL-C level was positively associated with AMD. The odds ratio was 2.00 (95%CI: 1.41-2.86). Instrumental variable analyses (Mendelian randomization approach) showed an increasing odds ratio of HDL-C and AMD, which was 7.15 (95%CI: 0.80-64.13). CONCLUSION:Being different with previous observational analysis, this study did not support the status of increasing serum HDL-C level as a risk factor for AMD by Mendelian randomization analysis.
Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank. Luo Shan,Au Yeung Shiu Lun,Zuber Verena,Burgess Stephen,Schooling Catherine Mary Journal of the American Heart Association Background Red blood cell (RBC) transfusion and erythropoiesis-stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome-wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best-fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance-weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05-1.41) with VTE. Sensitivity analyses (mendelian randomization-Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks. 10.1161/JAHA.120.016771
Association between celiac disease and systemic lupus erythematosus: a Mendelian randomization study. Inamo Jun Rheumatology (Oxford, England) 10.1093/rheumatology/keaa071
Vitamin C and primary prevention of cardiovascular disease: the case for Mendelian randomization. Santos Raul D European journal of preventive cardiology 10.1093/eurjpc/zwab089
Vitamin D and asthma: A Mendelian randomization study. Mao Yong,Zhan Yiqiang,Huang Yixiang Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 10.1016/j.anai.2017.05.018
Alzheimer's Disease and Rheumatoid Arthritis: A Mendelian Randomization Study. Cai Qixuan,Xin Zhuoyuan,Zuo Lin,Li Fan,Liu Bin Frontiers in neuroscience Alzheimer's disease (AD) is the most common neurodegenerative disease. In recent years, multiple pathway analyses of AD genome-wide association studies (GWAS) have been conducted, and provided strong support for immune pathways in AD. Rheumatoid arthritis (RA) is a chronic autoimmune disease. It is reported that antirheumatic drugs had protective effect on dementia in RA patients. However, observational studies have reported a controversial inverse relationship between AD and RA. In addition, Mendelian randomization studies have also been performed to evaluate the association of RA with AD. However, these studies reported inconsistent association of RA with AD. Until now, it is still unclear that AD is a causally associated with RA. Here, we performed a Mendelian randomization study to investigate the causal association of AD with RA. We analyzed the large-scale AD GWAS dataset (74,046 individuals) and RA GWAS dataset (58,284 individuals) from the European descent. However, we did not identify any significant association of AD with RA using inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. 10.3389/fnins.2018.00627
Exploring the Effects of Cigarette Smoking on Inflammatory Bowel Disease Using Mendelian Randomization. Crohn's & colitis 360 BACKGROUND:Previous observational evidence has suggested an association between smoking and inflammatory bowel disease (IBD). METHODS:We used observational techniques followed by Mendelian randomization to explore whether smoking is a causal factor in the development of IBD and its subtypes. RESULTS:In those who have ever smoked, we observed increased risk of IBD and, in current smokers, we observed increased risk of Crohn disease and decreased risk of ulcerative colitis. However, our Mendelian randomization analyses found little evidence that smoking affects the development of IBD. CONCLUSION:Overall, our results suggest that smoking does not causally influence the risk of IBD. 10.1093/crocol/otaa018
The Association Between Coronavirus Disease 2019 Infection and Blood Constituents: A Mendelian Randomization Analysis. The Journal of infectious diseases 10.1093/infdis/jiab189
Association between 25 Hydroxyvitamin D Concentrations and the Risk of COVID-19: A Mendelian Randomization Study. Liu Di,Tian Qiu Yue,Zhang Jie,Hou Hai Feng,Li Yuan,Wang Wei,Meng Qun,Wang You Xin Biomedical and environmental sciences : BES 10.3967/bes2021.104
Association of smoking with coronary artery disease and myocardial infarction: A Mendelian randomization study. European journal of preventive cardiology 10.1177/2047487320907747
Coagulation factors and the incidence of COVID-19 severity: Mendelian randomization analyses and supporting evidence. Zhou Yao,Qian Xinyi,Liu Zipeng,Yang Hongxi,Liu Tong,Chen Kexin,Wang Yaogang,Sham Pak Chung,Yu Ying,Li Mulin Jun Signal transduction and targeted therapy 10.1038/s41392-021-00640-1
Plasma circulating vitamin C levels and risk of multiple sclerosis: a two-sample Mendelian randomization analysis. Peng Haoxin,Wu Xiangrong,Wen Yaokai,Lin Jinsheng Multiple sclerosis and related disorders Whether vitamin C (VitC) supplementation can decrease multiple sclerosis (MS) risk remains controversial. Using data from large-scale genome-wide association studies, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between plasma circulating VitC levels and MS comprehensively. MR analysis did not support the causality between genetically determined per 1 standard deviation increase (around 20 mmol/L) in circulating VitC levels and MS risk (OR 0.88, 95%CI 0.65-1.18, P = 0.3822), supported by complementary sensitivity analyses, including the weighted median, MR-Egger, and MR Pleiotropy Residual Sum and Outlier test methods. 10.1016/j.msard.2021.103267
Gut Microbiota and Lung Cancer: A Mendelian Randomization Study. Zhou Huaqiang,Liu Jiaqing,Shen Jiayi,Fang Wenfeng,Zhang Li JTO clinical and research reports 10.1016/j.jtocrr.2020.100042
Psoriasis and COVID-19: A bidirectional Mendelian randomization study. Journal of the American Academy of Dermatology 10.1016/j.jaad.2022.10.019
Mendelian randomization analysis to examine for a causal effect of urate on bone mineral density. Dalbeth Nicola,Topless Ruth,Flynn Tanya,Cadzow Murray,Bolland Mark J,Merriman Tony R Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research In observational studies, serum urate concentrations are positively associated with bone mineral density (BMD) and reduced risk of fragility fractures, raising the possibility that urate is a direct mediator of bone density. We used Mendelian randomization analysis to examine whether urate has a causal effect on BMD. We analyzed data from the Generation 3 cohort in the Framingham Heart Study (FHS) (N = 2501 total; 1265 male, 1236 female). A weighted genetic urate score was calculated using the SLC2A9, ABCG2, SLC17A1, SLC22A11, and SLC22A12 single-nucleotide polymorphisms (SNPs) that explains 3.4% of the variance in serum urate. Mendelian randomization analysis was performed using the two-stage least squares method with >80% power at α = 0.05 to detect an effect size equivalent to that observed in the ordinary least squares analysis between serum urate and total femur BMD. A strong association between serum urate and BMD was observed in the crude ordinary least squares analysis (total femur crude beta = 0.47, p = 1.7E-51). In the two-stage least squares analysis using the weighted genetic urate score as the instrumental variable, no significant relationship was observed between serum urate and BMD (total femur crude beta =-0.36, p = 0.06). Similar findings were observed in both the male and female subgroups, and there was no evidence for causality when individual SNPs were analyzed. Serum urate is strongly associated with BMD. However, controlling for confounders by Mendelian randomization analysis does not provide evidence that increased urate has a causal effect on increasing BMD. 10.1002/jbmr.2434
Autoimmune Diseases and Lung Cancer: A Mendelian Randomization Study. Zhou Huaqiang,Liu Jiaqing,Zhang Yaxiong,Huang Yan,Zhang Li Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10.1016/j.jtho.2019.03.019
Addressing the causality of the association of atopic dermatitis with depression and anxiety using Mendelian randomization. Standl M The British journal of dermatology 10.1111/bjd.20622
A Bidirectional Mendelian Randomization Study of Selenium Levels and Ischemic Stroke. Frontiers in genetics Previous observational studies have shown that circulating selenium levels are inversely associated with ischemic stroke (IS). Our aims were to evaluate the causal links between selenium levels and IS, and its subtypes by Mendelian randomization (MR) analysis. We used the two-sample Mendelian randomization (MR) method to determine whether the circulating selenium levels are causally associated with the risk of stroke. We extracted the genetic variants (SNPs) associated with blood and toenail selenium levels from a large genome-wide association study (GWAS) meta-analysis. Inverse variance-weighted (IVW) method was used as the determinant of the causal effects of exposures on outcomes. A total of 4 SNPs (rs921943, rs6859667, rs6586282, and rs1789953) significantly associated with selenium levels were obtained. The results indicated no causal effects of selenium levels on ischemic stroke by MR analysis (OR = 0.968, 95% CI 0.914-1.026, p = 0.269). Meanwhile, there was no evidence of a causal link between circulating selenium levels and subtypes of IS. The MR study indicated no evidence to support the causal links between genetically predicted selenium levels and IS. Our results also did not support the use of selenium supplementation for IS prevention at the genetic level. 10.3389/fgene.2022.782691
Body Fat Composition and Risk of Rheumatoid Arthritis: Mendelian Randomization Study. Zhao Sizheng S,Maglio Cristina,Hughes David M,Cook James P Arthritis & rheumatology (Hoboken, N.J.) 10.1002/art.41766
Application and interpretation of Mendelian randomization approaches in exploring the causality between folate and coronary artery disease. The American journal of clinical nutrition 10.1093/ajcn/nqaa069
Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease. Manousaki Despoina,Mokry Lauren E,Ross Stephanie,Goltzman David,Richards J Brent Circulation. Cardiovascular genetics BACKGROUND:Observational studies support a possible association between decreased vitamin D levels and risk of coronary artery disease (CAD); however, it remains unclear whether this relationship is causal. We aimed to evaluate whether genetically lowered vitamin D levels influence the risk of CAD using a Mendelian randomization approach. METHODS AND RESULTS:In this 2-stage Mendelian randomization study, we first identified single-nucleotide polymorphisms associated with 25-hydroxyvitamin D (25OHD) levels in the SUNLIGHT consortium (n=33 996), then tested them for possible violation of Mendelian randomization assumptions. A count of risk alleles was tested for association with 25OHD levels in a separate cohort (n=2347). Alleles were weighted by their relative effect on 25OHD and tested for their combined effect on CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study (22 233 cases/64 762 controls). Four single-nucleotide polymorphisms were identified to be associated with 25OHD levels, all in or near genes implicated in 25OHD synthesis, transport or metabolism. A count of these risk alleles was strongly associated with 25OHD (n=2347, F-test statistic=49.7, P=2×10(-12)). None of the single-nucleotide polymorphisms associated with 25OHD levels were associated with CAD (all P values >0.6). The Mendelian randomization odds ratio (OR) for CAD was 0.99 (95% confidence interval, 0.84-1.17; P=0.93; I(2)=0) per SD decrease in log-transformed 25OHD levels. These results persisted after sensitivity analyses for population stratification and pleiotropy. CONCLUSIONS:Genetically lowered 25OHD levels were not associated with increased risk of CAD in a large, well-powered study, suggesting that previous associations between circulating 25OHD levels and CAD are possibly confounded or due to reverse causation. 10.1161/CIRCGENETICS.116.001396
Genetic liability to acne is associated with increased risk of inflammatory bowel disease: A Mendelian randomization study. Journal of the American Academy of Dermatology 10.1016/j.jaad.2022.04.050
Association between Alcohol Consumption and Serum Cortisol Levels: a Mendelian Randomization Study. Yang Jung Ho,Kweon Sun Seog,Lee Young Hoon,Choi Seong Woo,Ryu So Yeon,Nam Hae Sung,Park Kyeong Soo,Kim Hye Yeon,Shin Min Ho Journal of Korean medical science BACKGROUND:Several studies have reported conflicting results regarding the relationship between alcohol consumption and cortisol levels. However, the causality between alcohol consumption and cortisol levels has not been evaluated. METHODS:This study examined 8,922 participants from the Dong-gu Study. The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism was used as an instrumental variable for alcohol consumption. The association between the genetically predicted alcohol consumption and cortisol level was evaluated with Mendelian randomization (MR) using two-stage least squares regression. RESULTS:Alcohol consumption was positively associated with the serum cortisol level in both sexes in the observational analysis. In the MR analysis, the genetically predicted alcohol consumption was positively related to the cortisol level in men, with cortisol levels increasing by 0.18 μg/dL per drink per day. However, there was no relationship in women in the MR analysis. CONCLUSION:The predicted alcohol consumption according to the ALDH2 rs671 polymorphism was positively related to the cortisol levels, suggesting a causal relationship between alcohol consumption and cortisol levels. 10.3346/jkms.2021.36.e195
Serum Calcium Levels and Parkinson's Disease: A Mendelian Randomization Study. Frontiers in genetics BACKGROUND:Though increasing epidemiological studies have evaluated the correlation between serum calcium contents and Parkinson's disease (PD), the results are inconsistent. At present, whether there is a causal association between serum calcium content and PD remains undetermined. OBJECTIVE AND METHODS:This study was designed to explore the relationship between increased serum calcium contents and PD risk. In this present study, a Mendelian randomization trial was carried out using a large-scale serum calcium genome-wide association study (GWAS) dataset ( = 61,079, Europeans) and a large-scale PD GWAS dataset ( = 8,477, Europeans including 4,238 PD patients and 4,239 controls). Here, a total of four Mendelian randomization methods comprising weighted median, inverse-variance weighted meta-analysis (IVW), MR-Egger, and MR-PRESSO were used. RESULTS:Our data concluded that genetically higher serum calcium contents were not significantly related to PD. CONCLUSION:In conclusion, we provided genetic evidence that there was no direct causal relationship between serum calcium contents and PD. Hence, calcium supplementation may not result in reduced PD risk. 10.3389/fgene.2020.00824
Association of psoriasis with risk of COVID-19: A 2-sample Mendelian randomization study. Journal of the American Academy of Dermatology 10.1016/j.jaad.2022.01.048
Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study. Nutrients Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded. 10.3390/nu13072218
Sleep Duration and Stroke: Prospective Cohort Study and Mendelian Randomization Analysis. Stroke BACKGROUND AND PURPOSE:Studies of sleep duration in relation to specific types of stroke are scarce. Moreover, the results are inconclusive and causality remains unclear. Our objective was to investigate whether sleep duration is associated with risk of stroke and its types using observational and Mendelian randomization designs. METHODS:The prospective study included 79 881 women and men (45-79 years of age) who were followed up for incident stroke or death over a mean follow-up of 14.6 years (1 164 646 person-years) through linkage to Swedish Registers. For the Mendelian randomization study, single-nucleotide polymorphisms associated with sleep duration were identified from a genome-wide association study. Summarized data for genetic associations with stroke were obtained from publicly available data of the MEGASTROKE and the International Stroke Genetics Consortia. RESULTS:Compared with normal sleep duration, long sleep (≥9 hours per day) was associated with increased risk of total and ischemic stroke (hazard ratios [95% CI], 1.12 [1.03-1.22] and 1.14 [1.03-1.24], respectively), whereas short sleep (<7 h/d) was linked to higher risk of intracerebral hemorrhage (hazard ratio [95% CI], 1.21 [1.03-1.41]). The 2-sample Mendelian randomization analysis supported no causal association of short or long sleep duration with ischemic stroke as a whole. CONCLUSIONS:In a prospective study, long sleep duration was associated with increased risk of total and ischemic stroke, whereas short sleep was linked to increased risk of intracerebral hemorrhage. However, the Mendelian randomization analysis did not show a significant detrimental effect of short or long sleep duration on the risk of total stroke or stroke types. 10.1161/STROKEAHA.120.029902
Mendelian randomization analyses support causal relationships between blood metabolites and the gut microbiome. Nature genetics The gut microbiome has been implicated in a variety of physiological states, but controversy over causality remains unresolved. Here, we performed bidirectional Mendelian randomization analyses on 3,432 Chinese individuals with whole-genome, whole-metagenome, anthropometric and blood metabolic trait data. We identified 58 causal relationships between the gut microbiome and blood metabolites, and replicated 43 of them. Increased relative abundances of fecal Oscillibacter and Alistipes were causally linked to decreased triglyceride concentration. Conversely, blood metabolites such as glutamic acid appeared to decrease fecal Oxalobacter, and members of Proteobacteria were influenced by metabolites such as 5-methyltetrahydrofolic acid, alanine, glutamate and selenium. Two-sample Mendelian randomization with data from Biobank Japan partly corroborated results with triglyceride and with uric acid, and also provided causal support for published fecal bacterial markers for cancer and cardiovascular diseases. This study illustrates the value of human genetic information to help prioritize gut microbial features for mechanistic and clinical studies. 10.1038/s41588-021-00968-y
Gout and susceptibility and severity of COVID-19: A bidirectional Mendelian randomization analysis. The Journal of infection 10.1016/j.jinf.2022.05.042
Alcohol as a risk factor for pancreatitis. A systematic review and meta-analysis. JOP : Journal of the pancreas CONTEXT:Epidemiologic studies have suggested an association between alcohol consumption and pancreatitis, although the exact dose-response relationship is unknown. It also remains uncertain whether a threshold effect exists. OBJECTIVE:To conduct a systematic review and meta-analysis of epidemiologic studies on the association between alcohol consumption and the risk of pancreatitis. METHODS:We searched Ovid MEDLINE, EMBASE, CINAHL, Web of Science, ETOH and AIM. Studies were included if they reported quantifiable information on risk and related confidence intervals with respect to at least three different levels of alcohol intake. RESULTS:Six studies, including 146,517 individuals with 1,671 cases of pancreatitis, met the inclusion criteria. We found a monotonic and approximately exponential dose-response relationship between average volume of alcohol consumption and pancreatitis. However, in a categorical analysis the lower drinking categories were not significantly elevated, with an apparent threshold of 4 drinks daily. CONCLUSIONS:As the available evidence also indicates that the relationship is biologically plausible, these results support the existence of a link between alcohol consumption and the risk of pancreatitis.
Body mass index and the risk and prognosis of acute pancreatitis: a meta-analysis. Hong Shen,Qiwen Ben,Ying Jiang,Wei An,Chaoyang Tong European journal of gastroenterology & hepatology OBJECTIVE:BMI has been indicated to be associated with prognosis of acute pancreatitis (AP). However, the relationship between BMI and the risk of AP development is still unresolved. We examined this association by conducting a detailed meta-analysis. We also assessed its prognostic role by including more researches. METHODS:Studies were identified by searching MEDLINE and EMBASE through March 31, 2011. There were two end points in this meta-analysis: the risk of AP development and the outcome of AP (including severity, local complications, systemic complications, and mortality). Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS:Compared with normal weight individuals, obese individuals (BMI>30 kg/m²) had an increased risk of AP development (SRRs 1.34, 95% CI: 1.07-1.68), with significant heterogeneity among these studies (P=0.002, I²=77.2%). In addition, compared with nonobese patients, obese patients developed significantly more severe AP (SRRs 1.82, 95% CI: 1.44-2.30), systemic complications (SRRs 1.71, 95% CI: 1.17-2.50), local complications (SRRs 2.32, 95%CI: 1.79-3.00), and mortality (SRRs 2.21, 95% CI: 1.28-3.83). There was no heterogeneity among these studies. CONCLUSION:Findings from this meta-analysis indicated that obesity is not only associated with an increased risk of AP development, but it is also a poor prognostic factor for AP. 10.1097/MEG.0b013e32834b0e0e
Risk of development of acute pancreatitis with pre-existing diabetes: a meta-analysis. Xue Yuzheng,Sheng Yingyue,Dai Hong,Cao Haiyan,Liu Zongliang,Li Zhaoshen European journal of gastroenterology & hepatology OBJECTIVES:It is well established that acute pancreatitis (AP) often causes diabetes mellitus. However, whether pre-existing diabetes is associated with the development of AP remains unknown. To clarify the association of pre-existing diabetes and the development of AP, we carried out a meta-analysis of observational studies. METHODS:A computerized literature search was performed in MEDLINE (from 1 January 1966) and EMBASE (from 1 January 1974), through 31 January 2012. We also searched the reference lists of relevant articles. Summary relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q statistic and the I 2. RESULTS:A total of seven articles (10 523 incident cases of AP) were included in this meta-analysis. Analysis of seven studies indicated that, compared with nondiabetic individuals, diabetic individuals had a 92% increased risk of development of AP (95% CI 1.50-2.47). There was significant evidence of heterogeneity among these studies (P heterogeneity<0.001, I 2=93.0%). These increased risks were independent of alcohol use, gallstones, and hyperlipidemia. CONCLUSION:Although the current evidence supports a positive link between pre-existing diabetes and an increased risk of development of AP, additional studies, with a perfect design, are required before definitive conclusions can be drawn. 10.1097/MEG.0b013e328355a487
Type 2 diabetes mellitus and the risk of acute pancreatitis: a meta-analysis. Yang Lin,He Zhiyu,Tang Xulei,Liu Jingfang European journal of gastroenterology & hepatology AIMS:Epidemiological evidences indicate that individuals with diabetes may have an increased risk of acute pancreatitis. Therefore, we carried out a meta-analysis to examine the present evidence and to identify the association between type 2 diabetes mellitus and the risk of acute pancreatitis. METHODS:All observational studies and randomized-controlled trials evaluating the relationship between type 2 diabetes mellitus and the risk of acute pancreatitis were identified in PubMed (January 1966), Embase (January 1974), Web of Science (January 1986), and Cochrane Library, through March 2012. Relative risk with the corresponding 95% confidence interval was pooled using STATA 12.0. RESULTS:A total of seven observational studies with 15 298 024 patients were identified for the meta-analysis. Meta-analysis of these observational studies showed that type 2 diabetes mellitus was associated with an increased risk of acute pancreatitis (relative risk=1.84; 95% confidence interval 1.45-2.33; P=0.000), with significant heterogeneity (P=0.000, I=93.7%). The positive association was consistent in subgroup analyses according to the study design, geographic area, and sex. Our sensitivity analyses also confirmed the stability of the association. No significant publication bias was observed. CONCLUSION:These outcomes strongly support the relationship between type 2 diabetes mellitus and an increased risk of acute pancreatitis. More fundamental research should be carried out to elucidate the biological mechanisms. 10.1097/MEG.0b013e32835af154
Smoking and risk for acute pancreatitis: a systematic review and meta-analysis. Yuhara Hiroki,Ogawa Masami,Kawaguchi Yoshiaki,Igarashi Muneki,Mine Tetsuya Pancreas We aimed to better understand the relationship between smoking and a risk for acute pancreatitis (AP) in existing observational studies. We identified studies by searching the PubMed, Scopus, and Web of Science databases (from inception through August 31, 2013) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed-effects and random-effects models. A total of 5 studies met inclusion criteria for analysis. Both current smoking (summary RR, 1.74; 95% CI, 1.39-2.17; n = 5 studies) and former smoking (summary RR, 1.32; 95% CI, 1.03-1.71; n = 4 studies) were associated with an increased risk for AP. The positive association of current smoking and risk for AP remained when we limited the meta-analysis to studies that controlled for alcohol intake and body mass index (summary RR, 1.76; 95% CI, 1.31-2.36; n = 4 studies). Both current and former smoking are associated with increased risk for AP. Further investigations, both epidemiological and mechanistic, are needed to establish the extent to which the association can be explained by a causal link and whether smoking cessation can prevent the occurrence and development of AP. 10.1097/MPA.0000000000000176
Impact of smoking on the risk of pancreatitis: a systematic review and meta-analysis. PloS one BACKGROUND AND OBJECTIVE:Cigarette smoking may increase the risk of developing pancreatic cancer, although its impact on pancreatitis has only been discerned in recent years. However, the results of previous studies differ. We performed a meta-analysis to provide a quantitative pooled risk estimate of the association of cigarette smoking with pancreatitis. METHOD:A literature search of the MEDLINE and Embase databases was conducted, and studies were selected that investigated the association of cigarette smoking with pancreatitis. Summary relative risks (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS:Twenty-two studies were included. The summary RRs (95% CI) associated with ever, current and former smokers for acute and chronic pancreatitis (AP/CP) were as follows: 1.51 (1.10, 2.07)/3.00 (1.46, 6.17), 1.42 (1.08, 1.87)/2.72 (1.74, 4.24), and 1.22 (0.99, 1.52)/1.27 (1.00, 1.62), respectively. Moreover, studies that analyzed both AP and CP were also summarized: 1.73 (1.18, 2.54) for ever smokers, 1.67 (1.03, 2.68) for current smokers and 1.56 (1.16, 2.11) for former smokers, respectively. There was no evidence of publication bias across the studies. CONCLUSION:The evidence suggests a positive association of cigarette smoking with the development of pancreatitis. It is possible that smoking cessation may be a useful strategy for the management of pancreatitis. 10.1371/journal.pone.0124075
Meta-analysis: Tobacco smoking may enhance the risk of acute pancreatitis. Sun Xiaobing,Huang Xiaoquan,Zhao Ruifeng,Chen Beibei,Xie Qin Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] BACKGROUND AND AIM:Questions remain unclear about the association of smoking status and the development of acute pancreatitis (AP). We performed a meta-analysis of observational studies explore this association. METHODS:A computerized literature search was performed in MEDLINE and EMBASE through November 30, 2014. We also searched the reference lists of pertinent articles. We used a random-effects model to calculate the summary relative risks (SRRs) and their corresponding 95% confidence intervals (CIs). RESULTS:A total of 3690 incident cases of AP included 12 observational studies (6 case-control and 6 prospective cohort/nested case-control studies) were identified. Compared with never smokers, the summary RR estimates were 1.54 (95% CI, 1.31-1.80) for ever smokers, 1.71 (95% CI, 1.37-2.14) for current smokers, and 1.21 (95% CI, 1.02-1.43) for former smokers. Smoking is found to be a potential risk factor for alcohol use, idiopathic factors and drugs related AP, but not for gallstone related AP, in the ever and current smokers. A dose-response effect of tobacco use on the risk was ascertained: current smokers had a 40% (95% CI, 30%-51%) increased risk of AP for every additional 10 cigarettes per day. CONCLUSION:The present analysis suggests that smokers have an elevated risk of AP development. Further studies, however, are warranted before definitive conclusions can be drawn. 10.1016/j.pan.2015.03.001
Alcohol Consumption as a Risk Factor for Acute and Chronic Pancreatitis: A Systematic Review and a Series of Meta-analyses. Samokhvalov Andriy V,Rehm Jürgen,Roerecke Michael EBioMedicine BACKGROUND:Pancreatitis is a highly prevalent medical condition associated with a spectrum of endocrine and exocrine pancreatic insufficiencies. While high alcohol consumption is an established risk factor for pancreatitis, its relationship with specific types of pancreatitis and a potential threshold have not been systematically examined. METHODS:We conducted a systematic literature search for studies on the association between alcohol consumption and pancreatitis based on PRISMA guidelines. Non-linear and linear random-effect dose-response meta-analyses using restricted cubic spline meta-regressions and categorical meta-analyses in relation to abstainers were conducted. FINDINGS:Seven studies with 157,026 participants and 3618 cases of pancreatitis were included into analyses. The dose-response relationship between average volume of alcohol consumption and risk of pancreatitis was monotonic with no evidence of non-linearity for chronic pancreatitis (CP) for both sexes (p = 0.091) and acute pancreatitis (AP) in men (p = 0.396); it was non-linear for AP in women (p = 0.008). Compared to abstention, there was a significant decrease in risk (RR = 0.76, 95%CI: 0.60-0.97) of AP in women below the threshold of 40 g/day. No such association was found in men (RR = 1.1, 95%CI: 0.69-1.74). The RR for CP at 100 g/day was 6.29 (95%CI: 3.04-13.02). INTERPRETATION:The dose-response relationships between alcohol consumption and risk of pancreatitis were monotonic for CP and AP in men, and non-linear for AP in women. Alcohol consumption below 40 g/day was associated with reduced risk of AP in women. Alcohol consumption beyond this level was increasingly detrimental for any type of pancreatitis. FUNDING:The work was financially supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (R21AA023521) to the last author. 10.1016/j.ebiom.2015.11.023
Heavy Coffee Consumption and Risk of Pancreatitis: A Systematic Review and Meta-Analysis. Wijarnpreecha Karn,Panjawatanan Panadeekarn,Mousa Omar Y,Cheungpasitporn Wisit,Pungpapong Surakit,Ungprasert Patompong Digestive diseases and sciences BACKGROUND/OBJECTIVES:Heavy consumption of coffee may have a protective effect against pancreatitis although results from previous studies were inconsistent. This meta-analysis was conducted with the aim to summarize all available data. METHODS:This meta-analysis included observational studies that compared the risk of pancreatitis between heavy coffee-drinkers and individuals who were not heavy coffee-drinkers. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS:Out of 219 retrieved articles, four studies with 351,137 participants met the eligibility criteria and were included in the analysis. The risk of pancreatitis among heavy coffee-drinkers was significantly lower than individuals who were not heavy coffee-drinkers with the pooled RR of 0.78 (95% CI 0.67-0.91). The statistical heterogeneity between the studies was insignificant (I = 0%). CONCLUSIONS:This meta-analysis demonstrated a significantly decreased risk of pancreatitis among heavy coffee-drinkers. However, further investigations are still required to determine causality and potential clinical application. 10.1007/s10620-018-5214-1
Gene polymorphisms in the interleukins gene and the risk of acute pancreatitis: A meta-analysis. Zhu Xiaole,Hou Chaoqun,Tu Min,Shi Chenyuan,Yin Lingdi,Peng Yunpeng,Li Qiang,Miao Yi Cytokine Single nucleotide polymorphisms (SNPs) within the interleukins (IL) gene may affect the risk of acute pancreatitis. Many epidemiological studies have reported an association between the IL gene and acute pancreatitis risk, but the results remain inconsistent. Given the controversial available data, we carried out a meta-analysis to systematically evaluate and clarify the association between IL gene polymorphisms and AP. A systematic search of studies for this association was obtained from the PubMed, EMBASE, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases until June 1, 2017. We also searched the references of the included studies to identify additional studies. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to pool the effect size. Stata12.0 was used for whole statistical analysis. Fifteen studies that contained 3371 AP cases and 3506 controls were included in final combination. Overall, a significant association was found between the IL-8-251 T/A (rs4073) polymorphism, the IL-10-1082 A/G (rs1800896) polymorphism and the AP risk in four genetic models (homozygote model, recessive model, dominant model, allele model). Meanwhile, individuals with IL-1β+3954 C/T (rs1143634, (homozygote model, recessive model)), IL-1β -511 C/T (rs16944, (dominant model)) and IL-6-634C/G (rs1800796, (allele model)) polymorphism were associated with an increased risk of AP. No evidence of an association was found between IL and 10-592 C/A (rs1800872) and IL-10-819 C/T (rs1800871) polymorphism and AP risk. 10.1016/j.cyto.2018.12.003
Tobacco smoking and the risk of pancreatitis: A systematic review and meta-analysis of prospective studies. Aune Dagfinn,Mahamat-Saleh Yahya,Norat Teresa,Riboli Elio Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] BACKGROUND:Tobacco smoking has been associated with increased risk of pancreatitis in several studies, however, not all studies have found an association and it is unclear whether there is a dose-response relationship between increasing amount of tobacco smoked and pancreatitis risk. We conducted a systematic review and meta-analysis of prospective studies on tobacco smoking and pancreatitis to clarify the association. METHODS:PubMed and Embase databases were searched for relevant studies up to April 13th 2019. Prospective studies that reported adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for the association between tobacco smoking and pancreatitis were included and summary RRs were calculated using a random effects model. RESULTS:Ten prospective studies were included. The summary RR for acute pancreatitis was 1.49 (95% CI: 1.29-1.72, I = 68%, n = 7) for current smokers, 1.24 (95% CI: 1.15-1.34, I = 0%, n = 7) for former smokers, and 1.39 (95% CI: 1.25-1.54, I = 69%, n = 7) for ever smokers compared to never smokers. Similar results were observed for chronic pancreatitis and acute/chronic pancreatitis combined. The summary RR per 10 cigarettes per day was 1.30 (95% CI: 1.18-1.42, I = 42%, n = 3) and per 10 pack-years in current smokers was 1.13 (95% CI: 1.08-1.17, I = 14%, n = 4) for acute pancreatitis and results were similar for chronic pancreatitis and acute/chronic pancreatitis combined. CONCLUSIONS:These results suggest that tobacco smoking increases the risk of acute and chronic pancreatitis and acute and chronic pancreatitis combined and that there is a dose-response relationship between increasing number of cigarettes and pack-years and pancreatitis risk. 10.1016/j.pan.2019.09.004
Causality of genetically determined metabolites on anxiety disorders: a two-sample Mendelian randomization study. Journal of translational medicine BACKGROUND:Although anxiety disorders are one of the most prevalent mental disorders, their underlying biological mechanisms have not yet been fully elucidated. In recent years, genetically determined metabolites (GDMs) have been used to reveal the biological mechanisms of mental disorders. However, this strategy has not been applied to anxiety disorders. Herein, we explored the causality of GDMs on anxiety disorders through Mendelian randomization study, with the overarching goal of unraveling the biological mechanisms. METHODS:A two-sample Mendelian randomization (MR) analysis was implemented to assess the causality of GDMs on anxiety disorders. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, whereas four different GWAS datasets of anxiety disorders were the outcomes. Notably, all datasets were acquired from publicly available databases. A genetic instrumental variable (IV) was used to explore the causality between the metabolite and anxiety disorders for each metabolite. The MR Steiger filtering method was implemented to examine the causality between metabolites and anxiety disorders. The standard inverse variance weighted (IVW) method was first used for the causality analysis, followed by three additional MR methods (the MR-Egger, weighted median, and MR-PRESSO (pleiotropy residual sum and outlier) methods) for sensitivity analyses in MR analysis. MR-Egger intercept, and Cochran's Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. Bonferroni correction was used to determine the causative association features (P < 1.03 × 10). Furthermore, metabolic pathways analysis was performed using the web-based MetaboAnalyst 5.0 software. All statistical analysis were performed in R software. The STROBE-MR checklist for the reporting of MR studies was used in this study. RESULTS:In MR analysis, 85 significant causative relationship GDMs were identified. Among them, 11 metabolites were overlapped in the four different datasets of anxiety disorders. Bonferroni correction showing1-linoleoylglycerophosphoethanolamine (OR = 1.04; 95% CI 1.021-1.06; P = 4.3 × 10) was the most reliable causal metabolite. Our results were robust even without a single SNP because of a "leave-one-out" analysis. The MR-Egger intercept test indicated that genetic pleiotropy had no effect on the results (intercept = - 0.0013, SE = 0.0006, P = 0.06). No heterogeneity was detected by Cochran's Q test (MR-Egger. Q = 7.68, P = 0.742; IVW. Q = 12.12, P = 0.436). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < 0.001). In addition, two significant pathways, the "primary bile acid biosynthesis" pathway (P = 0.008) and the "valine, leucine, and isoleucine biosynthesis" pathway (P = 0.03), were identified through metabolic pathway analysis. CONCLUSION:This study provides new insights into the causal effects of GDMs on anxiety disorders by integrating genomics and metabolomics. The metabolites that drive anxiety disorders may be suited to serve as biomarkers and also will help to unravel the biological mechanisms of anxiety disorders. 10.1186/s12967-022-03691-2
Genetically predicted tea intake increases the risk of osteoarthritis: A Mendelian randomization study. Frontiers in genetics This study aimed to clarify the relationship between tea consumption and osteoarthritis (OA). Common single-nucleotide polymorphisms (SNPs) from the Open Genome-wide Association Studies database were obtained. Summary statistics on OA were retrieved from the second dataset that enrolled 50,508 participants (10,083 OA cases) of European ancestry. The causal association between tea intake and OA was tested using two-sample Mendelian randomization (MR) analysis. Tea consumption has adverse effects on OA. (inverse-variance weighted method: OR = 1.19, 95% CI = 1.08-1.30; weighted median method: OR = 1.22, 95% CI = 1.07-1.40). The MR-Egger regression intercept (MR intercept = -0.002; = 0.73) showed no evidence of directional pleiotropy. Moreover, no evidence of underlying heterogeneity in MR analysis was found according to Cochran's Q test and funnel and forest analyses. A genetically predicted high daily tea intake can increase the risk of OA. 10.3389/fgene.2022.1004392
Effects of Hyperthyroidism on Venous Thromboembolism: A Mendelian Randomization Study. Journal of immunology research Objective:Observational studies show the correlation between thyroid dysfunction and risk of venous thromboembolism. However, the causal effects remain uncertain. Our study was conducted to evaluate whether thyroid function and dysfunction were causally linked to the risk of venous thromboembolism. Methods:Publicly available summary data of thyrotropin (TSH) and free thyroxine (FT4), hypothyroidism, and hyperthyroidism were obtained from the ThyroidOmics Consortium and the UK Biobank. With single nucleotide polymorphisms (SNPs) as instrumental variables, the casual effects of genetically predicted TSH and FT4 and hypo- and hyperthyroidism on venous thromboembolism outcome were estimated through Mendelian randomization analysis methods (inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode). Cochran's Q test was performed to evaluate the heterogeneity and horizontal pleiotropy. Results:Our study selected 15 FT4-, 36 TSH-, 3 hyperthyroidism-, and 79 hypothyroidism-associated SNPs as instrumental variables. The IVW analysis results showed that the odds ratio of venous thromboembolism for hyperthyroidism was 1.124 (95% confidence interval: 1.019-1.240; = 0.019), demonstrating the casual effect of hyperthyroidism not FT4, TSH, and hypothyroidism on venous thromboembolism. No heterogeneity or horizontal pleiotropy was observed according to Cochran's Q test. Conclusion:Our Mendelian randomization analysis supports the causal effect of hypothyroidism on risk of venous thromboembolism. There is no evidence that genetically predicted TSH, FT4, and hypothyroidism have casual effects on venous thromboembolism. Future studies should be conducted to elucidate the underlying pathophysiological mechanisms. 10.1155/2022/2339678
Smoking, alcohol, and coffee consumption and pregnancy loss: a Mendelian randomization investigation. Fertility and sterility 10.1016/j.fertnstert.2022.09.025
Causal relationships of excessive daytime napping with atherosclerosis and cardiovascular diseases: a Mendelian randomization study. Sleep STUDY OBJECTIVES:Previous observational studies have found conflicting evidence on the relationship between daytime napping and incident cardiovascular diseases (CVDs), but it remains unclear whether these associations present causality. This study aims to verify whether and why there is a causal relationship between these parameters, and whether there is an etiological basis. METHODS:A two-sample Mendelian randomization analysis was performed using 79 single nucleotide polymorphisms associated with daytime napping. Summary-level data for coronary atherosclerosis, peripheral atherosclerosis, total CVD, and five CVD outcomes were obtained from the FinnGen study. Meta-analyses were aimed at investigating the relationships of excessive daytime napping with total CVD, coronary heart disease, myocardial infarction (MI), and stroke incidence. Subgroup, network meta-analysis (NMA) and trial sequential analysis (TSA) were also performed in this study. RESULTS:The inverse-variance weighted method demonstrated that a genetic predisposition to more frequent daytime napping was significantly associated with higher odds of coronary atherosclerosis (odds ratio [OR] = 1.55, 95% confidence interval [CI]: 1.11 to 2.17), MI (OR = 1.63, 95% CI: 1.06 to 2.50), and heart failure (OR = 1.80, 95%CI: 1.28 to 2.52). In NMA, an increased risk of developing CVD in people who napped for more than 60 min a day than those who did not nap was demonstrated and then supported by TSA results (summary relative risk = 1.98, 95% CI: 1.39 to 2.82). CONCLUSION:Habitual daytime napping is causally associated with an increased risk of incident CVD primarily via the development of coronary atherosclerosis. An average napping duration of more than 60 min is associated with an elevated risk of CVD in all participants. 10.1093/sleep/zsac257
Causal associations between disorders of lipoprotein metabolism and ten cardiovascular diseases. Frontiers in cell and developmental biology Disorders of lipoprotein metabolism have been linked with an increased risk of cardiovascular diseases (CVDs) but the causal association is unclear. In this study, we investigated the causal association between disorders of lipoprotein metabolism and CVDs using two-sample Mendelian randomization (MR). The exposure was obtained from Finn genome-wide association studies (14,010 cases, 197,259 controls), and the corresponding CVDs were extracted from the largest published genome-wide association studies. A random-effects inverse-variance weighted method was used for the main analyses with a complementary analysis using the weighted median and MR-Egger approaches. Multiple sensitivity analyses were performed to assess horizontal pleiotropy. The MR analysis indicated positive associations of disorders of lipoprotein metabolism with coronary artery disease (odds ratio [OR] 1.670, 95% confidence interval [CI] 1.373-2.031; < 0.001), aortic aneurysm (OR 1.394, 95% CI 1.199-1.619; < 0.001), heart failure (OR 1.20, 95% CI 1.115-1.294; < 0.001), hypertension (OR 1.011, 95% CI 1.006-1.091; < 0.001), old myocardial infarction (OR 1.004, 95% CI 1.002-1.007; = 0.001), and stroke (OR 1.002, 95% CI 1.001-1.003; = 0.002). There is a suggestive causal relationship between disorders of lipoprotein metabolism and atrial fibrillation (OR 1.047, 95% CI 1.006-1.091; = 0.026) and acute myocardial infarction (OR 1.003, 95% CI 1.001-1.005; = 0.012). There was limited evidence of a causal association between disorders of lipoprotein metabolism and peripheral vascular disease and venous thromboembolism. Our findings indicate a significant causal association between disorders of lipoprotein metabolism and many CVDs, including coronary artery disease, aortic aneurysm, heart failure, hypertension, old myocardial infarction, and stroke. These associations may be useful for development of treatment strategies that regulate lipoprotein metabolism in patients with CVD. 10.3389/fcell.2022.1023006
The relationship between lipoprotein(a) and risk of cardiovascular disease: a Mendelian randomization analysis. European journal of medical research BACKGROUND:Lipoprotein(a) [Lp(a)] is one of the residual risk factors for cardiovascular disease (CVD) in the setting of optimal low-density lipoprotein cholesterol (LDL-C). The association between Lp(a) and CVD is still in the exploratory phase, with few studies indicating a causal connection between Lp(a) and various CVD. METHODS:Lp(a) (n = 377,590) was a genome-wide association study (GWAS) based on European populations from Neale Lab. Large GWAS datasets for CVD, including aortic aneurysm(AA) (n = 209,366), atrial fibrillation(AF) (n = 1,030,836), coronary heart disease(CHD) (n = 361,194), secondary hypertension(HBP) (n = 164,147), heart failure(HF) (n = 208,178), ischemic stroke (IS) (n = 218,792), large artery atherosclerosis stroke(ISL) (n = 150, 765), small vessel stroke(ISS) (n = 198,048), lacunar stroke(LIS) (n = 225,419), and pulmonary embolism(PE) (n = 218,413) were also based on European populations. We performed separate univariate two-sample Mendelian randomization (MR) analysis for Lp(a) and CVD as described above. We evaluated this connection mainly using the random-effects inverse variance weighted technique(IVW1) with a 95% confidence interval (CI) for the odds ratio (OR). This was supplemented by MR-Egger, weighted median, maximum likelihood, penalized weighted median, and fixed-effects inverse variance weighted methods. MR-PRESSO offers another means of statistical detection. RESULTS:Our two-sample MR, which was predominately based on IVW1, revealed a causal relationship between Lp(a) and AA (OR = 1.005, 95%CI: 1.001-1.010, P = 0.009), CHD (OR = 1.003, 95%CI 1.001-1.004, P = 0.010), and ISL (OR = 1.003, 9 5%CI 1.002-1.004, P = 9.50E-11), in addition, there is no causal association with AF, HBP, HF, IS, ISS, LIS, or PE. Similar conclusions were reached by the MR-PRESSO method. CONCLUSION:This MR study suggested a causal relationship between Lp(a) and CHD, AA, and ISL, but not associated with AF, HF, IS, LIS, ISS, HBP, or PE. Our work further verifies the association between Lp(a) and various CVD, resulting in improved Lp(a) management and a reduction in the prevalence of CVD. 10.1186/s40001-022-00825-6
Association of triglyceride levels and prostate cancer: a Mendelian randomization study. BMC urology BACKGROUND:The association between triglyceride and prostate cancer (PCa) has been reported in observational studies. However, the causality from triglyceride on PCa remained unknown. METHOD:Two-sample Mendelian randomization (MR) was performed with triglyceride genome-wide association study (GWAS) data from 177,861 individuals and GWAS summary statistics of PCa from 463,010 individuals. Then, 48 single nucleotide polymorphisms (SNPs) of triglyceride were used as instrumental variables (IVs) to conduct MR analysis on PCa. Inverse-variance weighted (IVW), Weighted median, MR-Egger regression, Simple mode and Weighted mode were used for MR analysis. To verify the sensitivity of the data, heterogeneity test, pleiotropy test and leave-one-out sensitivity test were performed. RESULTS:Association for an effect of triglyceride on PCa risk was found in IVW (odds ratio [OR]: 1.002, 95% confidence interval (CI): 1.000-1.004, p = 0.016). However, opposing results were observed using the weighted median (OR: 1.001, 95% CI: 0.999-1.003, p = 0.499) and MR-Egger (OR: 0.999, 95% CI: 0.995-1.002, p = 0.401) approach. After MRPRESSO, the same result was obtained by using IVW method (OR: 1.002, 95% CI: 1.001-1.004, p = 0.004). CONCLUSIONS:The large MR analysis indicated that the potential causal effect of triglyceride on PCa. The odds of PCa would increase with high levels of triglyceride. 10.1186/s12894-022-01120-6
White blood cell count and chronic obstructive pulmonary disease: A Mendelian Randomization study. Computers in biology and medicine Blood leukocyte counts (e.g., eosinophil count) are important biomarkers for the onset, classification, and exacerbation of chronic obstructive pulmonary disease (COPD). The causal relationships between them are necessary for the development of COPD treatment strategy, but remain unclear. Here, we implement two-sample bi-directional univariable Mendelian Randomization (MR) and multivariable MR to investigate the causal relationships. Univariable MR find that elevated blood eosinophil count significantly increases the risk of COPD (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14-1.30, P = 1.54 × 10) and COPD-related hospitalization (OR = 1.44, 95% CI: 1.15-1.80, P = 1.36 × 10). Besides, it also significantly decreases the ratio of forced expiratory volume in the first second over forced vital capacity (FEV/FVC ratio) (OR = 0.942, 95% CI: 0.914-0.971, P = 1.02 × 10). These findings are fully supported by multivariate MR results. Interestingly, univariable MR reveals a weak causal relationship between elevated blood eosinophil count and COPD risk in younger people (<65 years) (OR = 1.39, 95% CI: 1.10-1.75, P = 5.52 × 10), but not older individuals (OR = 1.20, 95% CI: 0.926-1.55, P = 0.17). Finally, reverse univariable MR reveals the onset of COPD and the decreased FEV/FVC ratio both lead to increased blood neutrophil count (OR = 1.03, 95% CI: 1.01-1.05, P = 3.40 × 10 and OR = 0.947, 95% CI: 0.91-0.986, P = 8.75 × 10 respectively). In summary, this MR study demonstrates that high blood eosinophil count is an independent causal mediator of COPD risk, FEV/FVC decline, and COPD-related hospitalization. The increase in neutrophil count is induced by COPD onset or FEV/FVC decline. This suggests eosinophil, but not neutrophil, may be used as a therapeutic target for preventing the onset and exacerbation of COPD and FEV/FVC decline. Therefore, a non-neutrophil-targeted therapeutic strategy for neutrophilic COPD is required in the future. 10.1016/j.compbiomed.2022.106187
Causal association between rheumatoid arthritis and celiac disease: A bidirectional two-sample mendelian randomization study. Frontiers in genetics Rheumatoid Arthritis (RA) has been associated with Celiac Disease (CD) in previous observational epidemiological studies. However, evidence for this association is limited and inconsistent, and it remains uncertain whether the association is causal or due to confounding or reverse causality. This study aimed to assess the bidirectional causal relationship between RA and CD. In this two-sample Mendelian randomization (MR) study, instrumental variables (IVs) for RA were derived from a genome-wide association studies (GWAS) meta-analysis including 58,284 subjects. Summary statistics for CD originated from a GWAS meta-analysis with 15,283 subjects. The inverse-variance weighted (IVW) method was used as the primary analysis. Four complementary methods were applied, including the weighted-median, weighted mode, MR pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression, to strengthen the effect estimates. Positive causal effects of genetically increased RA risk on CD were derived [IVW odds ratio (OR): 1.46, 95% confidence interval (CI): 1.19-1.79, 3.21E-04]. The results of reverse MR analysis demonstrated no significant causal effect of CD on RA (IVW OR: 1.05, 95% CI: 0.91-1.21, 0.499). According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. This study reveals a causality of RA on CD but not CD on RA among patients of European descent. This outcome suggests that the features and indicators of CD should regularly be assessed for RA patients. 10.3389/fgene.2022.976579
Causal relationship between osteoporosis and osteoarthritis: A two-sample Mendelian randomized study. Frontiers in endocrinology Introduction:At present, clinical studies have confirmed that osteoporosis (OP) has an inverse relationship with osteoarthritis (OA), but it has not been proven from the point of view of genetics, so our study hopes to clarify the potential effect of OP on OA at the level of gene prediction through two-sample Mendelian randomization (MR) analysis. Methods:A two-sample MR was adopted to research the causal relationship of OP with OA (including total OA, knee OA and hip OA). All data come from a public shared database. Such traditional methods as simple and weighted models, inverse variance weighted, weighted median, and Mendelian Randomization (MR-Egger) regression were employed to assess the causal effect of OP on OA. We used the Pleiotrophy RESidual Sum and Outlier (MR-PRESSO) method and MR-Egger method to study sensitivity. The leave-one-out test is used to determine the influence of outliers. The heterogeneity was calculated by using Cochran Q statistics and MR-Egger regression in the inverse variance-weighted (IVW) method. > 0.05 indicates that there is a large heterogeneity. MR-Robust Adjustment Profile Score (RAPS) is stable to both systematic and specific multiplicity, so we used MR-RAPS as a supplementary method to verify the results of IVW. Results:According to the results of IVW, we found that there was a causal relationship between OP and total OA, and OP reduced the incidence of total OA (beta=-0.285, OR=0.751, value< 0.016). The MR estimation of the causal effect of OP on knee OA suggested that the genetic prediction of OP was negatively correlated with knee osteoarthritis (KOA) (IVW: beta=-6.11, OR=0.002, value< 0.016). The IVW results suggested that OP was causally related to hip OA, and OP had a protective effect on hip OA (beta=-5.48, OR=4.15e-3, value= 3.99e-3). Except for heterogeneity in the analysis of OP and knee OA, there was no horizontal pleiotropy or heterogeneity in the other analyses. Conclusion:We explored the causal relationship between OP and OA through a two-sample MR analysis and found that OP can reduce the incidence of OA (including knee OA and hip OA). 10.3389/fendo.2022.1011246
Non-alcoholic fatty liver disease is not a causal risk factor for psoriasis: A Mendelian randomization study of 108,835 individuals. Frontiers in immunology Background:Psoriasis is observationally associated with a higher risk of non-alcoholic fatty liver disease (NAFLD); however, the causal relationship between the two diseases remains unclear. Objective:We hypothesized that individuals with NAFLD or elevated liver fat content have higher risk of psoriasis and that NAFLD is a causal risk factor for psoriasis. We tested this using a Mendelian randomization approach. Methods:We included 108,835 individuals from the Danish general population, including 1,277 individuals with psoriasis and 802 individuals with NAFLD according to ICD codes. To estimate liver fat content, a subset of the participants (N = 7,416) also had a CT scan performed. First, we tested whether a diagnosis of NAFLD or elevated liver fat content was observationally associated with risk of psoriasis. Subsequently, we used the genetic variants and , both strongly associated with NAFLD and high liver fat content, to test whether NAFLD was causally associated with increased risk of psoriasis. Results:Observationally, individuals with vs. without a diagnosis of NAFLD had higher risk of psoriasis with an odds ratio of 2.03 (95% confidence interval 1.28-3.21). The risk of psoriasis increased in a stepwise manner with increasing liver fat content with an odds ratio of 5.00 (2.63-9.46) in individuals in the highest quartile of liver fat content compared to individuals in the lowest quartile. In genetic analyses, and were both associated with increased risk of NAFLD but not with increased risk of psoriasis. Conclusion:Observationally, a diagnosis of NAFLD or elevated liver fat content was associated with higher risk of psoriasis. However, using genetic variants as a proxy for NAFLD, we did not find evidence of a causal relationship between NAFLD and psoriasis. Thus, the observational association between NAFLD and psoriasis is presumably a result of shared confounding factors or reverse causation. 10.3389/fimmu.2022.1022460
The causal relationships between obstructive sleep apnea and elevated CRP and TNF-α protein levels. Annals of medicine BACKGROUND:Obstructive sleep apnea (OSA) and inflammation are closely related. This study aimed to evaluate the associations and causal effect between C-reactive protein (CRP) and tumour necrosis factor-alpha (TNF-α) levels andOSA. METHODS:Pooled analysis was conducted to compare the expression differences of CRP and TNF-α between OSA patients with different severity and controls, and between continuous positive airway pressure (CPAP) and non-CPAP interventions for OSA patients. Using published GWAS summary statistics, we conducted a bidirectional two-sample Mendelian Randomization (MR) to estimate the causal relationships between CRP and TNF-α levels and OSA risk. Effect estimates were evaluated using inverse-variance weighted (IVW) as primary method, and several other MR methods as sensitivity analysis. RESULTS:Both TNF-α (WMD [95%CI] = 5.86 [4.80-6.93] pg/ml,  < .00001) and CRP (WMD [95%CI] = 2.66 [2.15-3.17] mg/L,  < .00001), showed a significant increase in OSA patients compared with controls and this increasing trend was associated with OSA severity. Besides, compared to blank control (non-CPAP), CPAP treatment can reduce high TNF-α (WMD [95%CI]= -4.44 [-4.81, -4.07]pg/ml,  < .00001) and CRP (WMD [95%CI]= -0.91 [-1.65, -0.17] mg/l,  = .02) in OSA. Moreover, the primary MR analysis by IVW showed that OSA was the genetically predicted cause of elevated CRP (estimate: 0.095; 95% CI, [0.010-0.179];  = .029) using six SNPs as the instrument variable, which were repeated by weighted median (estimate: 0.053; 95% CI, [0.007, 0.100];  =.024) and MR RAPS (estimate: 0.109; 95% CI, [0.079, 0.140];  = 1.98x10). Besides, the causal effect from elevated CRP on increased OSA risk was almost significant by IVW (OR:1.053; 95% CI, [1.000, 1.111];  = .053). However, there were no causal associations between TNF-α and OSA from both directions. CONCLUSIONS:Increased CRP and TNF-α were associated with OSA severity and sensible to CPAP treatment. Also, OSA had a suggestive causal effect on elevated CRP. 10.1080/07853890.2022.2081873
Self-reported daytime napping, daytime sleepiness, and other sleep phenotypes in the development of cardiometabolic diseases: a Mendelian randomization study. European journal of preventive cardiology AIMS:Sleep disorders are associated with an increased risk of cardiometabolic diseases in observational studies, but the causality remains unclear. In this study, we leveraged two-sample Mendelian randomization (MR) analyses to assess the causal associations of self-reported daytime napping, daytime sleepiness, and other sleep phenotypes with cardiometabolic diseases including ischaemic stroke (IS), coronary artery disease (CAD), heart failure (HF), and Type 2 diabetes mellitus (T2DM). METHODS AND RESULTS:We selected genetic variants as instrumental variables for self-reported daytime napping, daytime sleepiness, morning person, insomnia, short sleep duration, and long sleep duration from European-descent genome-wide association studies (GWASs). Summary statistics for cardiometabolic diseases originated from four different GWASs with a total of 2 500 086 participants. We used the inverse-variance weighted method to explore the role of self-reported sleep phenotypes on the aetiology of cardiometabolic diseases in the main analyses, followed by several sensitivity analyses for robustness validation. Genetically predicted self-reported daytime napping [T2DM: OR, 1.56 (95% confidence interval, 1.21-2.02)], insomnia [IS: OR, 1.07 (1.04-1.11)]; CAD: OR, 1.13 (1.08-1.17); HF: OR, 1.10 (1.07-1.14); T2DM: OR, 1.16 (1.11-1.22); and short sleep duration [CAD: OR, 1.37 (1.21-1.55)] were causally associated with an elevated risk of cardiometabolic diseases. Moreover, genetically determined self-reported daytime sleepiness [CAD: OR, 2.05 (1.18-3.57); HF: OR, 1.82 (1.15-2.87)] and morning person [HF: 1.06 OR, (1.01-1.11)] had potential detrimental effect on cardiometabolic risks. CONCLUSION:Self-reported daytime napping, insomnia, and short sleep duration had causal roles in the development of cardiometabolic diseases, while self-reported daytime sleepiness and morning person was the potential risk factor for cardiometabolic diseases. 10.1093/eurjpc/zwac123
Alcohol consumption and smoking in relation to psoriasis: a Mendelian randomization study. The British journal of dermatology BACKGROUND:Alcohol consumption and smoking have been reported to be associated with psoriasis risk. However, a conclusion with high-quality evidence of causality could not be easily drawn from regular observational studies. OBJECTIVES:This study aims to assess the causal associations of alcohol consumption and smoking with psoriasis. METHODS:Genome-wide association study (GWAS) summary-level data for alcohol consumption (N = 941 280), smoking initiation (N = 1 232 091), cigarettes per day (N = 337 334) and smoking cessation (N = 547 219) was obtained from the GSCAN consortium (Sequencing Consortium of Alcohol and Nicotine use). The GWAS results for lifetime smoking (N = 462 690) were obtained from the UK Biobank samples. Summary statistics for psoriasis were obtained from a recent GWAS meta-analysis of eight cohorts comprising 19 032 cases and 286 769 controls and the FinnGen consortium, comprising 4510 cases and 212 242 controls. Linkage disequilibrium score regression was applied to compute the genetic correlation. Bidirectional Mendelian randomization (MR) analyses were conducted to determine casual direction using independent genetic variants that reached genome-wide significance (P < 5 × 10 ). RESULTS:There were genetic correlations between smoking and psoriasis. MR revealed a causal effect of smoking initiation [odds ratio (OR) 1·46, 95% confidence interval (CI) 1·32-1·60, P = 6·24E-14], cigarettes per day (OR 1·38, 95% CI 1·13-1·67, P = 0·001) and lifetime smoking (OR 1·96, 95% CI 1·41-2·73, P = 7·32E-05) on psoriasis. Additionally, a suggestive causal effect of smoking cessation on psoriasis was observed (OR 1·39, 95% CI 1·07-1·79, P = 0·012). We found no causal relationship between alcohol consumption and psoriasis (P = 0·379). The reverse associations were not statistically significant. CONCLUSIONS:Our findings provide causal evidence for the effects of smoking on psoriasis risk. What is already known about this topic? Alcohol consumption and smoking have been reported to be associated with psoriasis risk. Whether alcohol consumption and smoking have a causal effect on psoriasis risk remains unclear. What does this study add? This Mendelian randomization study shows a causal association between smoking, but not alcohol consumption, and the risk of developing psoriasis. Restricting smoking could be helpful in reducing the burden of psoriasis. 10.1111/bjd.21718
Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study. Osteoarthritis and cartilage OBJECTIVE:To provide some causal evidence concerning the effects of metformin on osteoarthritis (OA) using two metformin targets, namely AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15) as metformin proxies. METHODS:This is a 2-sample Mendelian randomization design. We constructed 44 AMPK-related variants genetically predicted in HbA1c (%) as instruments for AMPK and five variants strongly predicted GDF-15 as instruments for GDF-15. Summary-level data for three OA phenotypes, including OA at any site, knee OA, and hip OA were obtained from the largest genome-wide meta-analysis across the UK Biobank and arcOGEN with 455,211 Europeans. Main analyses were conducted using the inverse-variance weighted method. Weighted median and MR-Egger were conducted as sensitivity analyses to assess the robustness of our results. RESULTS:Genetically predicted AMPK were negatively associated with OA at any site (OR: 0.60; 95% CI: 0.43-0.83) and hip OA (OR: 0.42; 95% CI: 0.22-0.80), but with not knee OA (OR: 0.85; 95% CI: 0.49-1.50). Higher levels of genetically predicted GDF-15 reduced the risk of hip OA (OR: 0.95; 95% CI: 0.90-0.99), but not OA at any site (OR: 1.00; 95% CI: 0.98-1.02) and knee OA (OR: 1.02; 95% CI: 0.98-1.07). CONCLUSION:This study indicates that AMPK and GDF-15 can be potential therapeutic targets for OA, especially for hip OA, and metformin would be repurposed for OA therapy which needs to be verified in randomized controlled trials. 10.1016/j.joca.2022.06.010
Psoriasis may increase the risk of lung cancer: a two-sample Mendelian randomization study. Journal of the European Academy of Dermatology and Venereology : JEADV BACKGROUND:Although many studies have indicated that Psoriasis (PsO) could contribute to the risk of lung cancer, no study has reported a clear causal association between them. Our aim was to explore the potential causal association between PsO and the lung cancer risk using Mendelian randomization (MR) design. METHODS:To explore a causal association between the PsO and lung cancer, we used large-scale genetic summary data from genome-wide association study (GWAS), including PsO (n = 337 159) and lung cancer (n = 361 586), based on previous observational studies. Our main analyses were conducted by inverse-variance weighted (IVW) method with random-effects model, with a complementary with the other two analyses: weighted median method and MR-Egger approach. RESULTS:The results of IVW methods demonstrated that genetically predicted PsO was significantly associated with higher odds of lung cancer, with an odds ratio (OR) of 1.06 (95%CI, 1.01-1.12; P = 0.02). Weighted median method and MR-Egger regression also demonstrated directionally similar results (All P < 0.05). In addition, both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between PsO and lung cancer. CONCLUSIONS:Our study provided potential evidence between genetically predicted PsO and lung cancer, which suggested that enhanced screening for lung cancer allows early detection of lung cancer. 10.1111/jdv.18437
Serum Lipids and Risk of Incident Psoriasis: A Prospective Cohort Study from the UK Biobank Study and Mendelian Randomization Analysis. The Journal of investigative dermatology The association between dyslipidemia and psoriasis has been studied widely. However, which individual indicators of serum lipids determine an increasing risk of incident psoriasis is still underappreciated in prospective cohorts. On the basis of UK Biobank, we investigate the causal relationship between four serum lipids and incident psoriasis by Cox proportional hazard model and Mendelian randomization analysis. After adjusting for covariates, high-density lipoprotein deficiency (<1.0 mmol/l for men, <1.3 mmol/l for women) and high triglyceride level (≥1.7 mmol/l) at baseline were associated with 16.6% and 10.6% increased risk of incident psoriasis, respectively. The effects were more pronounced in women, with 16.9 and 19.7% additional risk of psoriasis, respectively. The effects in the younger group (aged <60 years) and obese group in women were also more pronounced. No similar effect was observed in low-density lipoprotein and total cholesterol. Our subsequent Mendelian randomization analysis reinforced the main finding that high-density lipoprotein deficiency and high triglyceride cause incident psoriasis genetically. In conclusion, serum high-density lipoprotein/triglyceride levels predict psoriasis, particularly in women, indicating a distinct role of lipids engaging in the pathogenesis of psoriasis modified by sex. More metabolic-targeted, sex-specific management of psoriasis is suggested in the future. 10.1016/j.jid.2022.06.015
Causal effect of non-alcoholic fatty liver disease on atrial fibrillation. European journal of internal medicine 10.1016/j.ejim.2022.07.007
Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nature human behaviour Growing evidence suggests that relative carbohydrate intake affects depression; however, the association between carbohydrates and depression remains controversial. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis using genetic variants associated with relative carbohydrate intake (N = 268,922) and major depressive disorder (N = 143,265) from the largest available genome-wide association studies. MR evidence suggested a causal relationship between higher relative carbohydrate intake and lower depression risk (odds ratio, 0.42 for depression per one-standard-deviation increment in relative carbohydrate intake; 95% confidence interval, 0.28 to 0.62; P = 1.49 × 10). Multivariable MR indicated that the protective effect of relative carbohydrate intake on depression persisted after conditioning on other diet compositions. The mediation analysis via two-step MR showed that this effect was partly mediated by body mass index, with a mediated proportion of 15.4% (95% confidence interval, 6.7% to 24.1%). These findings may inform prevention strategies and interventions directed towards relative carbohydrate intake and depression. 10.1038/s41562-022-01412-9
Psoriasis and progression of Parkinson's disease: a Mendelian randomization study. Journal of the European Academy of Dermatology and Venereology : JEADV BACKGROUND:Epidemiological studies have suggested psoriasis was associated with an increased risk of Parkinson's disease (PD). However, whether psoriasis has an effect on PD progression is not explored yet. OBJECTIVES:To evaluate the causal role of psoriasis in PD progression. METHODS:We conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association study of psoriasis (N = 33 394), age at onset (N = 28 568) and progression (N = 4093) of PD. RESULTS:One standard deviation increase in genetically determined psoriasis risk was significantly associated with faster progression to dementia (OR = 1.07, 95% CI: 0.1.03-1.1, P = 4.71E-04). Meanwhile, higher psoriasis risk was nominally associated with faster progression of PD measured by time to Hoehn and Yahr stage 3 (OR = 1.05, 95% CI: 1.02-1.08, P = 1.53E-03) and depression (OR = 1.06, 95% CI: 1.02-1.11, P = 1.77E-03) of PD. The results were robust under all sensitivity analyses. CONCLUSIONS:These results suggested psoriasis accelerated overall progression of PD, and increased risk of dementia and depression of PD. A deeper understanding of neuroinflammation and immune response is likely to elucidate the potential pathogenesis of PD progression and identify novel therapeutic targets. 10.1111/jdv.18459
Alcohol consumption and subclinical and clinical coronary heart disease: a Mendelian randomization analysis. European journal of preventive cardiology AIMS:The potential effect of alcohol consumption on coronary heart disease (CHD) remains unclear. We used the variant rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) as an instrument to investigate the causal role of alcohol intake in subclinical and clinical CHD. METHODS:We conducted two Mendelian randomization studies: a cross-sectional study of coronary artery calcification (CAC) on computed tomography of 1029 healthy men (mean age, 63.8 years) and a case-control study of 421 men with CHD [acute coronary syndrome (ACS) or stable angina pectoris] who underwent coronary revascularization and 842 age-matched male controls. RESULTS:In the CAC study, medians (25%tiles, 75%tiles) of alcohol consumption by ALDH2-rs671 *2 homozygotes [n = 86 (8.4%)], *1*2 heterozygotes [n = 397 (38.5%)], and *1 homozygotes [n = 546 (53.1%)] were 0.0 (0.0, 0.0), 28.0 (0.0, 129.0), and 224.0 (84.0, 350.0) g/week, respectively. In age-adjusted Poisson regression with robust error variance, compared with *2 homozygotes, relative risks for prevalent CAC score >0, ≥100, and ≥300 in *1 homozygotes were 1.29 (95% confidence interval, 1.06-1.57), 1.76 (1.05-2.96), and 1.81 (0.80-4.09), respectively. In age-adjusted ordinal logistic regression for CAC distributions, we observed higher odds among *1 homozygotes [odds ratio, 2.19 (1.39-3.46)] and even among *1*2 heterozygotes [1.77 (1.11-2.82)] compared with *2 homozygotes. In the case-control study, conditional logistic regression revealed lower prevalence of *1 homozygotes among men with CHD [odds ratio, 0.54 (0.35-0.82)], especially ACS [0.46 (0.27-0.77)], than controls. CONCLUSION:Our findings indicate a positive association of alcohol consumption with CAC burden but an inverse association with clinical CHD, especially ACS. 10.1093/eurjpc/zwac156
Genetic evidence that the causal association of educational attainment with reduced risk of Alzheimer's disease is driven by intelligence. Neurobiology of aging Alzheimer's disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end of their life dementia free. However, evidence obtained from the observational studies does not take into account how risk factors are correlated with one another, and whether they causally contribute to increased AD risk. In this study, we determine whether the relationship between previously speculated AD risk factors and AD susceptibility is consistent with causality using large-scale genetic data. We focus on educational attainment (EA), intelligence and household income which have been previously shown to be causally associated with AD. Using GWAS-by-subtraction and Multivariable Mendelian Randomization we show that of these, only the cognitive component of EA (intelligence) is independently causally associated with AD. This work has ramifications for the modifiability of lifestyle risk factors for AD. 10.1016/j.neurobiolaging.2022.07.011
The chicken or the egg: disentangling the relationship between smoking, alcohol consumption and psoriasis using Mendelian randomization. The British journal of dermatology 10.1111/bjd.21805
Severe COVID-19 increases the risk of schizophrenia. Psychiatry research The coronavirus SARS-CoV-2 invades the central nervous system, impacting the mental health of COVID-19 patients. We performed a two-sample Mendelian randomization analysis to assess the potential causal effects of COVID-19 on schizophrenia. Our analysis indicated that genetic liability to hospitalized COVID-19 was associated with an increased risk for schizophrenia (OR: 1.11, 95% CI: 1.02-1.20, P = 0.013). However, genetic liability to SARS-CoV-2 infection was not associated with the risk of schizophrenia (1.06, 0.83-1.37, P = 0.643). Severe COVID-19 was associated with an 11% increased risk for schizophrenia, suggesting that schizophrenia should be assessed as one of the post-COVID-19 sequelae. 10.1016/j.psychres.2022.114809
Genetic determinants of circulating metabolites and the risk of stroke and its subtypes. European journal of neurology BACKGROUND AND PURPOSE:Circulating metabolites have been implicated in stroke pathogenesis, but their genetic determinants are understudied. Using a Mendelian randomization approach, our aim was to provide evidence for the relationship of circulating metabolites and the risk of stroke and its subtypes. METHODS:Genetic instruments of 102 circulating metabolites were obtained from a genome-wide association study, including 24,925 European individuals. Stroke was extracted from the MEGASTROKE dataset (67,162 cases; 454,450 controls) and a lacunar stroke dataset (7338 cases; 254,798 controls). The magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury were evaluated by a genome-wide association study of white matter hyperintensities (N = 18,381), fractional anisotropy (N = 17,663), mean diffusivity (N = 17,467) and brain microbleeds (N = 25,862). The inverse-variance weighted method Mendelian randomization was used as the primary analytical method, and directional pleiotropy and heterogeneity were examined in sensitivity analyses. RESULTS:A genetic predisposition to a higher level of cholesterol in small and low-density lipoprotein (LDL) was associated with risk of stroke (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.08-1.21, p = 5.98 × 10 ), especially for large-artery atherosclerotic stroke (OR 1.34, 95% CI 1.19-1.52, p = 1.90 × 10 ). Total lipids in LDL particles were also associated with risk of stroke. A genetically determined higher cholesterol level in high-density lipoprotein (HDL-C) was associated with risk of intracerebral haemorrhage (OR 1.74, 95% CI 1.23-2.45, p = 1.66 × 10 ). No statistically significant association was found between genetic predisposition to circulating metabolites and magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury. CONCLUSIONS:Genetically determined levels of lipids in small LDL were associated with the risk of stroke, suggesting that a therapeutic strategy targeting small LDL levels may be crucial for stroke prevention. HDL-C was positively associated with the risk of intracerebral haemorrhage. 10.1111/ene.15549
Assessing the causal associations of obstructive sleep apnea with serum uric acid levels and gout: a bidirectional two-sample Mendelian randomization study. Seminars in arthritis and rheumatism OBJECTIVE:Multiple observational studies have reported the close associations of obstructive sleep apnea (OSA) with serum uric acid (SUA) levels and gout. However, the causal nature and direction remains unclear. METHODS:A bidirectional two-sample Mendelian randomization (MR) study was performed, based on publicly available genome-wide association studies (GWAS) summary statistics, to investigate whether OSA is causally related to SUA levels, gout and vice versa. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results. Moreover, multivariable MR (MVMR) was utilized to evaluate the independent causal effect of OSA on SUA and gout after adjusting for body mass index (BMI), hypertension, type 2 diabetes (T2D), coronary artery disease (CAD), and chronic kidney disease (CKD). RESULTS:Genetically predicted OSA liability was significantly associated with increased levels of SUA (IVW method: β = 0.19, 95% CI = 0.11 - 0.26, P = 7.24 × 10) and risk of gout [IVW method: odds ratio (OR) = 1.75 95% CI = 1.13 - 2.69, P = 0.01] in univariable MR. The MVMR results suggested that OSA retained its significant association with increased SUA levels, whereas the significant association between OSA and gout was attenuated to null after adjusting for BMI and T2D. No causal effect of OSA on SUA levels and gout was found in the reverse direction. CONCLUSIONS:Our findings suggest that OSA was causally associated with increased levels of SUA, but was not independently associated with gout risk. 10.1016/j.semarthrit.2022.152095
Shared genetics between classes of obesity and psychiatric disorders: A large-scale genome-wide cross-trait analysis. Journal of psychosomatic research AIMS:Epidemiological studies demonstrate an association between classes of obesity and psychiatric disorders, although little is known about shared genetics and causality of association. Thus, we aimed to investigate shared genetics and causal link between different classes of obesity and psychiatric disorders. METHODS:We used genome-wide association study (GWAS) summary data range from 9725 to 500,199 sample sizes of European descent, conducted a large-scale genome-wide cross-trait association study to investigate genetic overlap between the classes of obesity and anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, anxiety disorders and Tourette syndrome. We conducted transcriptome-wide association study analysis (TWAS) to identified variants regulated gene expression in those related disorders. Finally, pathway enrichment analysis to identified major pathways. RESULTS:In the combined analysis, we replicated 211 previously reported loci and discovered 58 novel independent loci that were associated with all three classes of obesity and related psychiatric disorders. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to exocrine/endocrine, digestive, circulatory, adipose, digestive, respiratory, and nervous systems, such as DCC, NEGR1, INO80E. Mendelian randomization analyses suggested that there may be a two-way or one-way causal relationship between obesity and psychiatric disorders. CONCLUSION:This large-scale genome-wide cross-trait analysis identified shared genetics and potential causal links between classes of obesity and psychiatric disorders (attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, major depressive disorder, schizophrenia, and obsessive-compulsive disorder). Such shared genetics suggests potential new biological functions in common among them. 10.1016/j.jpsychores.2022.111032
Causal influence of dietary habits on the risk of major depressive disorder: A diet-wide Mendelian randomization analysis. Journal of affective disorders BACKGROUND:Extensive observational evidence links diet quality to the risk for major depressive disorder (MDD), while clinical trials show that dietary improvement can improve depressive symptoms. However, due to issues with blinding dietary trials, confirming a causal relationship for diet's influence on MDD requires further research. Thus, we systemically investigated the bi-directional causal relationships between dietary habits and MDD by using two-sample Mendelian randomization (MR). METHODS:We collected publicly available genome-wide association studies' summary statistics for dietary habits from UK Biobank (n = 449,210) and MDD from the Psychiatric Genomics Consortium (n = 142,646). We used a weighted median approach to synthesize MR estimates across genetic instruments. For the robustness of our results, we compared weighted median results with results from the inverse-variance weighted, the weighted mode, and MR-PRESSO. RESULTS:There was moderate evidence that beef intake has a protective effect on MDD. There was weak but detectable evidence that cereal intake has a protective effect on MDD, while non-oily fish intake might increase the risk of MDD. We did not observe any causal effect of MDD on dietary habits. LIMITATIONS:Our study may suffer from the violation of assumptions of MR due to horizontal pleiotropy; therefore, we did several sensitivity analyses to detect and minimize the bias. CONCLUSIONS:In this two-sample MR analysis, we observed that higher beef intake may be protective against MDD. However, MDD did not appear to affect dietary habits. Potential mechanisms need to be further investigated to support our novel findings. 10.1016/j.jad.2022.09.109
Genetic liability to sedentary behavior in relation to myocardial infarction and heart failure: A mendelian randomization study. Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Observational studies have indicated that sedentary behavior is associated with myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). Nevertheless, whether these associations are causal remain controversial, due to confounding factors (e.g., physical activity) and reverse causality. METHODS AND RESULTS:Instrumental variables were obtained from the largest genome-wide association studies of sedentary behavior (408,815 individuals) to date. We obtained summary statistics of MI from the CARDIoGRAMplusC4D consortium (171,875 individuals), HF from the HERMES Consortium (977,323 individuals), and AF from the Atrial Fibrillation Consortium (588,190 individuals). The inverse-variance weighted method was applied to obtain Mendelian randomization (MR) estimates, and other statistical methods were conducted in the sensitivity analyses. The main analyses were repeated using data from the FinnGen study. Multivariable MR analysis and mediation analysis were performed to evaluate the role of physical activity and other confounders. Genetically determined television watching was associated with MI (odds ratio [OR], 1.38; 95% CI, 1.19-1.59; p = 1.9 × 10) and HF (OR, 1.23; 95%CI, 1.09-1.38; p = 7.0 × 10) but not AF. The main results kept robust in most sensitivity analyses. The effect of sedentary behavior on MI and HF was partly mediated by body mass index (BMI). No consistent evidence was found for the causal effect of computer use and driving on MI, HF, or AF. CONCLUSIONS:Genetic liability to prolonged television watching is associated with higher risks of MI and HF. Interventions for reducing television watching time, such as public education and awareness campaigns, should be further investigated. 10.1016/j.numecd.2022.07.005
A causal relationship between alcohol intake and type 2 diabetes mellitus: A two-sample Mendelian randomization study. Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:We investigated whether alcohol intake has a causal relationship with type 2 diabetes mellitus (T2DM) risk in adults of the Korean Genomic Epidemiology Study using two-sample Mendelian randomization (MR) analysis. METHODS AND RESULTS:Daily alcohol intake was calculated based on the type, average amount, and frequency of alcohol consumption for six months before the interview. The participants were divided into low- and high-alcohol intake of 20 g/day. After adjusting for the covariates related to T2DM, the independent genetic variants (instrumental variables) related to alcohol intake were explored by GWAS analysis in a city hospital-based cohort (n = 58,701). SNPs with a significant level of p-value <5 × 10 and linkage disequilibrium of r < 0.001 were retrieved. MR methods were used to analyze the causality between alcohol intake and the T2DM risk, and the heterogeneity and leave-one-out sensitivity analyses were conducted in Ansan/Ansung plus rural cohorts (n = 13,598). High alcohol intake increased T2DM risk when the inverse-variance weighted (P = 0.012) and weighted median (P = 0.034) methods were used, but not when the MR-Egger method was used. No significant heterogeneity and horizontal pleiotropy between alcohol intake and T2DM were detected. A single genetic variant did not affect the causal association in a leave-one-out sensitivity analysis. CONCLUSION:This study supports that heavy alcohol intake appears to be causally associated with T2DM risk. 10.1016/j.numecd.2022.08.013
Association of autoimmune diseases with Alzheimer's disease: A mendelian randomization study. Journal of psychiatric research BACKGROUND:Alzheimer's disease may have an autoimmune component, but the association is unclear. OBJECTIVE:The objective of this Mendelian randomization (MR) study was to evaluate the association of liability to autoimmune diseases with Alzheimer's disease. METHODS:A systematic search was done using PubMed to identify autoimmune diseases that have been suggested as associated with Alzheimer's disease. Genetic predictors of these autoimmune diseases were obtained from the largest and most recent genome-wide association studies (GWAS). Genetic associations with clinically-diagnosed Alzheimer's disease were obtained from the International Genomics of Alzheimer's Project GWAS (21982 cases; 41944 controls); and with parental and sibling history of Alzheimer's disease from the UK Biobank GWAS (27696 maternal, 14338 paternal and 2171 sibling cases). MR estimates were obtained using inverse variance weighting, MR-Egger and weighted median. To address possible selection bias due to inevitably recruiting only survivors, the analysis was repeated in younger people, i.e., UK Biobank siblings and adjusting for competing risk of Alzheimer's disease. RESULTS:Of the 7 autoimmune diseases considered, liability to psoriasis and sarcoidosis were not associated with Alzheimer's disease. Some evidence was found for liability to multiple sclerosis being associated with higher risk and liability to Sjogren's syndrome with lower risk of Alzheimer's disease. Associations found for liability to giant cell arteritis, type 1 diabetes and rheumatoid arthritis were inconsistent in sensitivity analyses. CONCLUSION:Liability to multiple sclerosis and Sjogren's syndrome could be associated with Alzheimer's disease. The underlying mechanisms, such as the role of myelin and neuroinflammation, should be further investigated. 10.1016/j.jpsychires.2022.09.052
Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses. Circulation BACKGROUND:End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS:Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS:There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min·1.73 m, compared with those with eGFR between 60 and 105 mL·min·1.73 m. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min·1.73 m, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min·1.73 m lower genetically predicted eGFR, but not for those with eGFR >105 mL·min·1.73 m. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS:In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function. 10.1161/CIRCULATIONAHA.122.060700
Psoriasis and cardiovascular disease risk in European and East Asian populations: evidence from meta-analysis and Mendelian randomization analysis. BMC medicine BACKGROUND:Psoriasis has been linked to cardiovascular disease (CVD), including coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF). However, available studies regarding this relationship have shown inconsistent results. Therefore, in this report, we performed a comprehensive review of the literature to assess the effects of psoriasis on risk of these CVDs. METHODS:A search of literature until 24 December 2021 was done in PubMed, the Cochrane Library, Web of Science, Google Scholar, and Embase. Within European and East Asian populations, meta-analyses of observational studies assessing correlations between psoriasis and various CVD risk factors were conducted. Mendelian randomization (MR) was then employed to assess the causative impact of genetic pre-disposition for psoriasis on these CVD risk factors. RESULTS:The results of the meta-analyses indicated that, in both the European and East Asian populations, psoriasis was significantly linked to an elevated risk in the incidence of CAD (RR = 1.51, 95% confidence interval (CI): 1.04-2.18, p = 0.028 and RR = 1.91, 95% CI: 1.62-2.25, p < 0.001) and MI (RR = 1.23, 95% CI: 1.04-1.46, p = 0.017 and RR = 2.17, 95% CI: 1.44-3.28, p < 0.001). A positive genetic relationship of psoriasis with CAD was found in European individuals (IVW OR:1.03; 95% CI: 1.01-1.06, p = 0.005) and in East Asian individuals (IVW OR:1.18; 95% CI: 1.03-1.32, p = 0.031). We also established that psoriasis was causally linked with an elevated risk of MI (IVW OR:1.05; 95% CI: 1.01-1.09, p = 0.026) in the European population as determined using an MR approach. Moreover, our MR results were congruent with the null findings from the meta-analysis assessing associations of psoriasis with HF risk. CONCLUSIONS:This research work provides preliminary evidence that psoriasis and CVD have a common genetic origin and that targeted psoriasis treatment might improve cardiovascular outcomes. These results not only increase our knowledge of the genetic underpinnings linking a comorbidity of psoriasis with CVD but also suggests a novel approach for CVD prevention. 10.1186/s12916-022-02617-5
COVID-19 and the risk of Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Annals of clinical and translational neurology BACKGROUND:The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on the healthcare system, economy, and society. Studies have reported that COVID-19 may cause various neurologic symptoms, including cognitive impairment. We aimed to assess the causal effect of COVID-19 on neurodegenerative diseases using two-sample Mendelian randomization (MR) study. METHODS:Genetic variants were obtained from genome-wide association studies (GWAS) summary-level data and meta-analyses. We used the inverse variance-weighted (IVW) method as the primary analysis to estimate causal effects. Sensitivity analyses were performed to make the conclusions more robust and reliable. RESULTS:We found that the COVID-19 infection phenotype was associated with a higher risk of AD and inverse associated with the risk of ALS and MS. The hospitalized COVID-19 phenotype was associated with the risk of AD and wasn't associated with ALS and MS. We also found that the severe COVID-19 (main analysis) phenotype was associated with the AD outcome from UK biobank datasets but was not associated with other outcomes. The severe COVID-19 infection phenotype, the severe COVID-19 (subtype analysis) phenotype and the hospitalization risk of COVID-19 were not associated with each outcome. CONCLUSION:This MR study suggests a potential association between genetically predicted COVID-19 and a higher risk of AD and a reduced risk of ALS and MS. Further elucidations of this association and underlying mechanisms may inform public health messages to prevent COVID-19 and AD. 10.1002/acn3.51688
Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study. Alzheimer's research & therapy Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations. 10.1186/s13195-022-01101-9
Vascular endothelial growth factor and the risk of venous thromboembolism: a genetic correlation and two-sample Mendelian randomization study. Thrombosis journal BACKGROUND:The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE. METHODS:Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran's Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE. RESULTS:LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95% confidence interval (CI), 1.009-1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (β = -0.021, 95% CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates. CONCLUSIONS:Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted. 10.1186/s12959-022-00427-6
Independent Associations of Education, Intelligence, and Cognition With Hypertension and the Mediating Effects of Cardiometabolic Risk Factors: A Mendelian Randomization Study. Hypertension (Dallas, Tex. : 1979) BACKGROUND:Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown. METHODS:Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions. RESULTS:Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40-0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education; 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses. CONCLUSIONS:Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education. 10.1161/HYPERTENSIONAHA.122.20286
Mendelian randomization study on the effect of tumor necrosis factor on schizophrenia. Psychiatric genetics OBJECTIVE:Previous observational studies have shown that the levels of tumor necrosis factor (TNF) increased in patients with schizophrenia. The present two-sample Mendelian randomization (MR) study aims to identify the causal link between TNF and schizophrenia. METHODS:To date, the largest genome-wide association study (GWAS) for TNF (n = 23 141) and for schizophrenia (53 386 cases and 77 258 controls) was used. All participants were of European ancestry. The MR-egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and heterogeneity, respectively. Weighted median and inverse variance weighted (IVW) were used to evaluate the causal association of TNF with schizophrenia. RESULTS:We found no significant pleiotropy or heterogeneity of all three selected plasma TNF genetic instrumental variants in breast cancer GWAS. Interestingly, the odds ratio (OR) = 1.517 with 95% confidence interval (CI), 1.006-2.288 and P = 0.047 of schizophrenia correspond to one unit increase in natural log-transformed TNF levels using IVW method. The increased trend was further proven using weighted median (OR = 1.585; 95% CI, 1.017-2.469; P = 0.042). Reverse MR analysis shows no causal effect of schizophrenia on plasma TNF levels. CONCLUSIONS:Our analysis suggested a causal association between genetically increased TNF signaling and increased risk of schizophrenia in the European population. Thus, TNF may be a potential risk for schizophrenia. 10.1097/YPG.0000000000000329
Bidirectional Association between Major Depressive Disorder and Gastroesophageal Reflux Disease: Mendelian Randomization Study. Genes BACKGROUND:Observational research has found a bidirectional relationship between major depressive disorder and gastroesophageal reflux disease; however, the causal association of this relationship is undetermined. AIMS:A bidirectional Mendelian randomization study was performed to explore the causal relationships between major depressive disorder and gastroesophageal reflux disease. METHODS:For the instrumental variables of major depressive disorder and gastroesophageal reflux disease, 31 and 24 single-nucleotide polymorphisms without linkage disequilibrium ( ≤ 0.001) were selected from relevant genome-wide association studies, respectively, at the genome-wide significance level ( ≤ 5 × 10). We sorted summary-level genetic data for major depressive disorder, gastroesophageal reflux disease, gastroesophageal reflux disease without esophagitis, and reflux esophagitis from meta-analysis study of genome-wide association studies involving 173,005 individuals (59,851 cases and 113,154 non-cases), 385,276 individuals (80,265 cases and 305,011 non-cases), 463,010 individuals (4360 cases and 458,650 non-cases), and 383,916 individuals (12,567 cases and 371,349 non-cases), respectively. RESULTS:Genetic liability to major depressive disorder was positively associated with gastroesophageal reflux disease and its subtypes. Per one-unit increase in log-transformed odds ratio of major depressive disorder, the odds ratio was 1.31 (95% confidence interval [CI], 1.19-1.43; = 1.64 × 10) for gastroesophageal reflux disease, 1.51 (95% CI, 1.15-1.98; = 0.003) for gastroesophageal reflux disease without esophagitis, and 1.21 (95% CI, 1.05-1.40; = 0.010) for reflux esophagitis. Reverse-direction analysis suggested that genetic liability to gastroesophageal reflux disease was causally related to increasing risk of major depressive disorder. Per one-unit increase in log-transformed odds ratio of gastroesophageal reflux disease, the odds ratio of major depressive disorder was 1.28 (95% confidence interval, 1.11-1.47; = 1.0 × 10). CONCLUSIONS:This Mendelian randomization study suggests a bidirectional causal relationship between major depressive disorder and gastroesophageal reflux disease. 10.3390/genes13112010
Human blood metabolites and lacunar stroke: A Mendelian randomization study. International journal of stroke : official journal of the International Stroke Society BACKGROUND:Lacunar stroke accounts for a quarter of all strokes, but little is known about the underlying pathological mechanisms. Analysis of serum metabolites may allow better understanding of the underlying biological processes. Mendelian randomization (MR) can provide information on the causality of associations. AIMS:To identify causal relationships between serum metabolites and lacunar stroke. METHODS:We applied a two-sample MR analysis to evaluate relationships between 486 serum metabolites and lacunar stroke. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of the exposure on the outcome, while sensitivity analyses were performed using MR-Egger, weighted median, and MR-PRESSO to eliminate the pleiotropy. We also performed a metabolic pathway analysis to identify potential metabolic pathways. RESULTS:We identified 15 known (8 risk and 7 protective) and 14 unknown serum metabolites associated with lacunar stroke. Among the known risk metabolites, two were lipids (1-linoleoylglycerophosphoethanolamine and dihomo-linolenate (20:3n3 or n6)), five amino acids (kynurenine, isobutyrylcarnitine, aspartate, trans-4-hydroxyproline, and 3-methyl-2-oxovalerate), and one peptide (ADSGEGDFXAEGGGVR). The known protective metabolites included four lipids (4-androsten-3beta,17beta-diol disulfate 1, 1-palmitoleoylglycerophosphocholine, adrenate (22:4n6), and glycodeoxycholate), one amino acid (methionine), and two exogenous metabolites (homostachydrine and 2-methoxyacetaminophen sulfate). Metabolic pathway analysis identified several pathways that might be involved in the disease. CONCLUSION:We identified eight risk and seven protective human serum metabolites associated with lacunar stroke. Isobutyrylcarnitine was positively associated with an increased risk of lacunar stroke. In addition, 3-methyl-2-oxovalerate and aspartate may be involved in the disease pathogenesis through metabolic pathways. 10.1177/17474930221140792
Smoking, alcohol, and coffee consumption and pregnancy loss: a Mendelian randomization investigation. Fertility and sterility 10.1016/j.fertnstert.2022.09.026
Investigating modifiable pathways in psoriasis: A Mendelian randomization study. Journal of the American Academy of Dermatology BACKGROUND:Potentially modifiable risk factors have previously been investigated only in conventional observational studies. OBJECTIVE:To assess whether genetically predicted exposures to modifiable factors are associated with the risk of psoriasis. METHODS:Two-sample Mendelian randomization (MR) analysis. RESULTS:An increased risk of psoriasis was noted for genetically predicted lifetime smoking index (odds ratio [OR] = 2.11; 95% confidence interval [CI], 1.28-3.51), childhood (OR  = 1.40; 95% CI, 1.14-1.71) and adult body mass index (OR  = 1.63; 95% CI, 1.32-2), waist (OR  = 1.86; 95% CI, 1.31-2.64), and hip circumference (OR  = 1.55; 95% CI, 1.15-2.07). Protective association was also reported between genetically predicted longer sleep duration (OR  = 0.56; 95% CI 0.37-0.84) and increased years of education (OR  = 0.78; 95% CI, 0.62-0.98). This effect of education persisted in multivariable MR after adjusting for genetic predictors of smoking and adult body mass index (OR = 0.72; 95% CI, 0.56-0.92). LIMITATIONS:It was not possible to stratify for psoriasis severity. CONCLUSION:Smoking cessation and prevention of obesity are important strategies for decreasing the incidence of psoriasis. Similarly, targeting education inequality is expected to lead further to reductions in cases of psoriasis. 10.1016/j.jaad.2022.11.010
Increased brain volume from higher cereal and lower coffee intake: shared genetic determinants and impacts on cognition and metabolism. Cerebral cortex (New York, N.Y. : 1991) It is unclear how different diets may affect human brain development and if genetic and environmental factors play a part. We investigated diet effects in the UK Biobank data from 18,879 healthy adults and discovered anticorrelated brain-wide gray matter volume (GMV)-association patterns between coffee and cereal intake, coincidence with their anticorrelated genetic constructs. The Mendelian randomization approach further indicated a causal effect of higher coffee intake on reduced total GMV, which is likely through regulating the expression of genes responsible for synaptic development in the brain. The identified genetic factors may further affect people's lifestyle habits and body/blood fat levels through the mediation of cereal/coffee intake, and the brain-wide expression pattern of gene CPLX3, a dedicated marker of subplate neurons that regulate cortical development and plasticity, may underlie the shared GMV-association patterns among the coffee/cereal intake and cognitive functions. All the main findings were successfully replicated. Our findings thus revealed that high-cereal and low-coffee diets shared similar brain and genetic constructs, leading to long-term beneficial associations regarding cognitive, body mass index (BMI), and other metabolic measures. This study has important implications for public health, especially during the pandemic, given the poorer outcomes of COVID-19 patients with greater BMIs. 10.1093/cercor/bhac005
Genetically predicted coffee consumption and amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration : Observational studies have indicated an association between coffee consumption and amyotrophic lateral sclerosis (ALS). Nevertheless, whether the association is causal is still unclear. We conducted a Mendelian randomization study to explore whether coffee consumption is causally related to ALS. : Two genome-wide association studies (GWASs) investigating coffee consumption ( = 129,422 and 375,833, respectively) were adopted to define instrumental variables for coffee consumption (high vs. infrequent/no, 1 cup/day increase, and 50% increase). Summary-level data for ALS were adopted from a large GWAS of ALS with a total of 20,806 cases and 59,804 controls. : Genetically predicted higher coffee consumption was not associated with ALS. The ORs were 1.02 (95% CI: 0.93-1.13;  = 0.649) for high vs. infrequent/no, 0.98 (95% CI: 0.84-1.15;  = 0.822) for 1 cup/day increase, 0.97 (95% CI: 0.79-1.19;  = 0.766) for 50% increase. Sensitivity analyses yielded consistent results. No pleiotropic bias and heterogeneity were observed. : Using multiple approaches and sensitivity analyses, our MR results show that genetically predicted coffee consumption was not associated with ALS. Further studies are warranted to explore the effect of coffee consumption on ALS progression. 10.1080/21678421.2022.2047204
Causal Association between Whole-Body Water Mass and Sleep Apnea: A Mendelian Randomization Study. Annals of the American Thoracic Society Growing evidence has suggested that body water content plays a critical role in sleep apnea. However, the causal relationship has not been established. This study aimed to investigate whether increased whole-body water mass is causally associated with a higher risk of sleep apnea using two-sample Mendelian randomization (MR) analysis. Body water mass (BWM)-associated genetic instruments were extracted from a genome-wide association study conducted by Neale Lab, which incorporates 331,315 individuals of European ancestry. Genetic variants for sleep apnea were derived from the FinnGen dataset. MR analysis was performed using inverse variance-weighted and weight median methods, respectively. MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier tests were applied to evaluate the directional pleiotropy. In addition, we performed a multivariable MR analysis that includes body mass index, snoring, and waist-to-hip ratio as covariate exposures to address their confounding effects. To elucidate mechanisms of the association between BWM and sleep apnea, we further conducted MR analysis on common edematous diseases. MR estimates showed that per standard deviation increase in BWM led to an increase in the risk of sleep apnea by 49% (odds ratio [OR], 1.490; 95% confidence interval [CI], 1.308-1.696;  = 1.75 × 10). The result after MR-Pleiotropy Residual Sum and Outlier correction further supports their causal association (OR, 1.414; 95% CI, 1.253-1.595;  = 1.76 × 10). In addition, the multivariable MR analysis indicates a significant causal association between a higher BWM and increased risk of sleep apnea (OR, 1.204; 95% CI, 1.031-1.377;  = 0.036). Genetic predisposition to a higher BWM was also causally related to increased risk of edematous diseases. Our results suggested that increased BWM is a potential risk factor for sleep apnea. Pathologic edema is a possible intermediate factor mediating this causal association. 10.1513/AnnalsATS.202112-1331OC
Association between COVID-19 and telomere length: A bidirectional Mendelian randomization study. Journal of medical virology Several traditional observational studies suggested an association between COVID-19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID-19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of critically ill COVID-19 (n = 1 388 342) and LTL (n = 472 174) of European ancestry. The random-effects inverse-variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single-nucleotide polymorphisms (SNPs) of genome-wide significance as instrumental variables for critically ill COVID-19, we did not find a significant association of COVID-19 on LTL (β = 0.0075, 95% confidence interval [CI]: -0.018 to 0.021, p = 0.733). Likewise, using 97 SNPs of genome-wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID-19 (odds ratio = 1.00, 95% CI: 0.79-1.28, p = 0.973). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID-19 and LTL in either direction. 10.1002/jmv.28008
Causal relationship between type 1 diabetes and hypothyroidism: A Mendelian randomization study. Clinical endocrinology OBJECTIVES:Although an association between type 1 diabetes (T1D) and hypothyroidism has been found in multiple observational studies, whether T1D plays a causal role in the development of hypothyroidism remains uncertain. Therefore, this Mendelian randomization (MR) study aimed to investigate the causal association between T1D and hypothyroidism. METHODS:Independent single-nucleotide polymorphisms associated with T1D with genome-wide significance were selected as instrumental variables from a large genome-wide association study (GWAS) of T1D. Hypothyroidism GWAS summary statistics were obtained from the Thyroidomics Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for estimating the effect of the exposure on the outcome. We also used MR-Egger, the weighted median method, MR-Robust, and other methods to confirm the results. RESULTS:T1D had a positive causal association with hypothyroidism [IVW, odds ratio (OR) = 1.083, 95% confidence interval (CI), 1.046-1.122; p &lt; .001]. MR-Egger regression indicated that directional pleiotropy did not bias the result (intercept = 0.006; p = .295). The causal association was verified in an independent validation set (IVW, OR = 1.099, 95% CI, 1.018-1.186; p = .017). The results were robust according to various MR methods, and the results of the reverse MR analysis did not support reverse causation (p &gt; .05). CONCLUSIONS:The MR analysis results indicated a causal association between T1D and hypothyroidism. Therefore, it is recommended that patients with T1D undergo thyroid function tests regularly to minimize the risk of undiagnosed hypothyroidism among young patients with T1D. 10.1111/cen.14801
Blood Pressure Mediated the Effects of Urinary Uromodulin Levels on Myocardial Infarction: a Mendelian Randomization Study. Hypertension (Dallas, Tex. : 1979) BACKGROUND:The causal links between urinary uromodulin (uUMOD) and cardiovascular disease (CVD) are still not clarified. METHODS:We first assessed the relationship between uUMOD and CVD using bidirectional 2-sample Mendelian randomization. Then, multivariable Mendelian randomization and product of the coefficients methods were used to investigate the role of blood pressure in mediating the effect of uUMOD on CVD. RESULTS:1-unit higher uUMOD level was associated with a higher risk of myocardial infarction (MI), with an odds ratio of 1.08 ([95% CI, 1.02-1.14]; =0.009), while MI was not associated with uUMOD levels in reverse. Our study did not support the causal effects of uUMOD on other CVD outcomes, including coronary artery disease, atrial fibrillation, heart failure, and ischemic stroke. In multivariable Mendelian Randomization, the direct effects of uUMOD on MI were attenuated to null after introducing systolic blood pressure or diastolic blood pressure. Mediation analysis showed that the indirect effect of uUMOD on MI mediated by systolic blood pressure or diastolic blood pressure was 1.05 ([95% CI, 1.04-1.06]; mediation proportion=69%) and 1.07 ([95% CI, 1.05-1.08]; mediation proportion=87%), respectively. Similar results were found in sensitivity analysis based on different sets of genetic instruments. CONCLUSIONS:Our findings provide evidence for the effect of higher uUMOD on increasing blood pressure, which mediates a consequent effect on MI risk in the general population. Further studies are necessary to verify the associations between uUMOD and other CVD outcomes. 10.1161/HYPERTENSIONAHA.122.19670
Circulating Insulin-Like Growth Factor 1 Levels and Migraine Risk: A Mendelian Randomization Study. Neurology and therapy INTRODUCTION:Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method. METHODS:A total of 431 independent variants from 363,228 unrelated individuals in the UK Biobank were used as genetic instruments for circulating IGF1 levels. Summary-level data for migraines were obtained from two independent studies with 10,536 and 28,852 migraine cases, respectively. RESULTS:Mendelian randomization using inverse-variance weighting showed that increased IGF1 levels were significantly associated with decreased risk of migraines in both outcome datasets (odds ratio 0.905, 95% confidence interval 0.842-0.972, p = 0.006; odds ratio 0.929, 95% confidence interval 0.882-0.979, p = 0.006). Although some other robust Mendelian randomization methods did not demonstrate a significant association, no unbalanced horizontal pleiotropy was found by Mendelian randomization-Egger regression (p values for horizontal pleiotropy 0.232 and 0.435). The effect was confirmed in additional analyses including multivariable Mendelian randomization analyses. CONCLUSION:This two-sample Mendelian randomization study showed that genetically determined increased IGF1 levels are causally associated with decreased migraine risk. Future randomized controlled trials are warranted to confirm the benefits of IGF1 administration on migraines. 10.1007/s40120-022-00398-w
Vitamin D and heart failure: A two-sample mendelian randomization study. Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:The relationship between vitamin D and heart failure (HF) has attracted significant interest, but the association between the two in previous studies remains uncertain. Therefore, we used two-sample Mendelian randomization (MR) to investigate a causal association between 25-hydroxyvitamin D (25OHD) and HF risk. METHODS AND RESULTS:This study utilized summary statistics from the most extensive genome-wide association studies for 25OHD and HF. To make the results more reliable, we used several methods based on three assumptions for MR analysis. We also used the multivariable MR adjusting for hypertension, BMI, diabetes, chronic kidney disease to further elucidate the association between 25OHD and HF. Considering the potential pleiotropy, we performed an MR analysis with conditionally independent genetic instruments at core genes to further determine the relationship between vitamin D and heart failure. We found that per 1 SD increase in standardized log-transformed 25OHD level, the relative risk of HF decreased by 16.5% (OR: 0.835, 95% Cl: 0.743-0.938, P = 0.002), and other MR methods also showed consistent results. The multivariable MR also reported that per 1 SD increase in standardized log-transformed 25OHD level, the relative risk of HF decreased. And the scatter plots showed a trend towards an inverse MR association between 25OHD levels, instrumented by the core 25OHD genes, and HF. CONCLUSION:In summary, we found a potential inverse association between elevated 25OHD levels and the risk of HF, which suggested that timely 25OHD supplementation or maintaining adequate 25OHD concentrations may be an essential measure for HF prevention in the general population. 10.1016/j.numecd.2022.08.003
Insomnia, sleep duration, and risk of anxiety: A two-sample Mendelian randomization study. Journal of psychiatric research BACKGROUND:The effect of insomnia and sleep duration on risk of anxiety has been assessed based on traditional epidemiological studies. However, the inconsistent conclusions do not establish causal associations. This study aimed to explore the causal associations of insomnia, short sleep, and long sleep with anxiety. METHODS:We used summary statistics from three large-scale genome-wide association studies (GWAS) of European ancestry to perform a two-sample Mendelian randomization (MR) study. MR analyses were mainly conducted with the inverse-variance-weighted (IVW) method. To evaluate the robustness of our findings, we performed the weighted-median approach, the MR-Egger method, and the MR-robust adjusted profile score (MR-RAPS) method for sensitivity analyses. RESULTS:There was a statistically significant association of genetically predicted insomnia with anxiety using the IVW method (OR = 1.36, 95% CI = 1.23-1.51, P < 0.001). Genetically predicted short sleep was potentially associated with anxiety using IVW method (OR = 1.67, 95% CI = 1.08-2.60, P = 0.022). However, sensitivity analyses did not find the causal association of short sleep with anxiety (all P > 0.053). We did not observe a statistically significant causal association of genetically predicted long sleep with anxiety (OR = 0.91, 95% CI = 0.48-1.74, P = 0.775). CONCLUSIONS:We found strong evidence that insomnia but not short sleep and long sleep has a causal effect on anxiety. The characteristics of insomnia should be incorporated into anxiety prevention and intervention strategies, which have important public health significance. 10.1016/j.jpsychires.2022.08.012
Association between telomere length and insomnia: A mendelian randomization and colocalization study. Sleep medicine BACKGROUND:Previous studies have suggested a potential association between sleep and telomere length (TL), but its genetic basis remains unclear. In this study, we aimed to explore the genetic correlation and potential causal association between TL and insomnia. METHODS:The genome-wide association study (GWAS) datasets of TL and insomnia-related traits were used, including insomnia, snoring, daytime dozing and napping. Based on the polygenic risk scores (PRS) of TL, linear regression and linkage disequilibrium score (LDSC) regression were used to preliminarily explore the association between TL and insomnia parameters in the UK Biobank cohort. Then, we investigated the causal association between TL and insomnia by mendelian randomization (MR) analysis and colocalization analysis. RESULTS:In the UK Biobank cohort, the association between TL and insomnia was observed in the female samples (t = 2.968, P = 3.00 × 10). LDSC detected a genetic correlation between short TL and insomnia (Rg = -9.27 × 10, P = 8.00 × 10). We found no evidence supporting significant causal association between insomnia and TL in IVW method (b = -5.95 × 10, P = 0.57), with horizontal pleiotropy and heterogeneity tests indicating the validity of our MR study. Finally, rs12638862 was classified as colocalized by COLOC (PP4 = 0.99), and TERC may be involved in regulating the association between insomnia and TL. CONCLUSIONS:Our study found no evidence for causal association between insomnia and TL in individuals of European ancestry. We detected a candidate gene associated with both insomnia and TL, providing novel clues for understanding the roles of this association. 10.1016/j.sleep.2022.09.002
Unbiased metabolome screen links serum urate to risk of Alzheimer's disease. Neurobiology of aging Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease caused by a combination of genetic and environmental risk factors. The serum metabolome refers to a set of small-molecules which are an important determinant of cellular health. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 376 metabolites which were population matched with 2 GWAS studies of AD. For each metabolite we performed 2-sample MR (2SMR) using an inverse variance weighted (IVW) estimate for significance testing. After Bonferroni multiple testing correction one metabolite was causally linked to AD in both GWAS: serum urate. This result was supported by robust 2SMR measures and sensitivity analyses. We applied 2SMR to test for a causal relationship between serum urate and other neurodegenerative diseases: Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS). In ALS but not PD we identified a nominally significant link between serum urate and disease-risk, although in this case increased serum urate was protective. We conclude that serum urate is a modulator of risk for neurodegeneration. Our work has implications for the design of preventative interventions. 10.1016/j.neurobiolaging.2022.09.004
The association between circulating docosahexaenoic acid and lung cancer: A Mendelian randomization study. Clinical nutrition (Edinburgh, Scotland) BACKGROUND:Lung cancer is a malignant tumor with a high incidence, it is vital to identify modifiable and avoidable risk factors for primary prevention, which can significantly lower the risk of cancer by preventing exposure to hazards and altering risky behavior. Some observational studies suggest that an increase in docosahexaenoic acid (DHA) consumption can reduce lung cancer risk. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To evaluate the link between DHA and lung cancer, we have undertaken this analysis to examine the causal association between DHA and the risk of lung cancer using a two-sample Mendelian randomization (MR) framework. METHODS:We performed a two-sample MR analysis to evaluate the causal effect of plasma DHA levels on lung cancer risk. For the exposure data, we extracted genetic variants as instrumental variables (IVs) that are strongly associated with DHA from a large-scale genome-wide association study (GWAS). We obtained the corresponding effect estimates for IVs on the risk of lung cancer with 11,348 cases and 15,861 controls. Finally, we applied Mendelian randomization analysis to obtain preliminary MR results and performed sensitivity analyses to verify the robustness of our results. RESULTS:According to the primary MR estimates and further sensitivity analyses, a higher serum DHA level was associated with a higher risk of lung cancer [OR = 1.159, 95% CI (1.04-1.30), P = 0.01]. For lung adenocarcinoma, the results also showed a close correlation between the DHA level and lung adenocarcinoma [OR = 1.277, 95% CI (1.09-1.50), P = 0.003], but it was not statistically significant for squamous cell carcinoma [OR = 1.071, 95% CI (0.89-1.29), P = 0.467]. CONCLUSIONS:Our study revealed that plasma DHA is positively associated with the risk of lung cancer overall, especially for lung adenocarcinoma. This study provides new information to develop dietary guidelines for primary lung cancer prevention. 10.1016/j.clnu.2022.09.004
Mendelian randomization study on the causal effects of systemic lupus erythematosus on major depressive disorder. Journal of human genetics The vast majority of epidemiological studies suggested a link between systemic lupus erythematosus (SLE) and major depressive disorder (MDD). However, the causality for SLE on the risk of MDD remained unknown due to confounding factors or reverse causality. Herein, we investigated the causality between SLE and MDD in those of European ancestry by a Mendelian randomization (MR) approach. Summary genetic data of cases with SLE/MDD were derived from independent largest public genome-wide association study. Forty-six single nucleotide polymorphisms associated with SLE were used as instrumental variables. The main causal inference was carried out using the MRE-IVW method. Additional, reverse-direction MR and multivariable MR analyses were further performed. Result indicated that SLE was causally associated with a lower risk of MDD (using the MRE-IVW method, odds ratio [OR] = 0.983, 95% confidence interval [CI] = 0.974-0.991, p = 1.18 × 10). Complementary analysis found no heterogeneity or horizontal pleiotropy. Multivariate MR analysis yielded consistent results (OR =  0.981; 95% CI = 0.969-0.993; p = 2.75 × 10). Reverse-direction MR analysis suggested non-causal relationship of MDD on the risk of SLE (using the IVW method, OR = 0.846, 95% CI = 0.345-2.072; p = 0.714). Thus, this is the first study providing evidence of potential causal links between SLE and MDD and further related research is needed. 10.1038/s10038-022-01080-7
Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study. BMC medicine BACKGROUND:Epidemiological studies have reported an association between amyotrophic lateral sclerosis (ALS) and different autoimmune disorders. This study aims to explore the causal relationship between autoimmune disorders and ALS using Mendelian randomization (MR). METHODS:To test the genetically predicted effects of liability towards immune-related outcomes on ALS risk, we used summary statistics from the largest European genome-wide association studies (GWAS) for these disorders in a two-sample MR setting. To do this, we extracted single nucleotide polymorphisms (SNPs) from the GWAS, which strongly associated with the 12 traits, and queried their effects in a large European ALS GWAS (27,265 cases and 110,881 controls). To avoid bias in our MR instruments related to the complex linkage disequilibrium structure of the human leukocyte antigen (HLA) region, we excluded SNPs within this region from the analyses. We computed inverse-variance weighted (IVW) MR estimates and undertook sensitivity analyses using MR methods robust to horizontal pleiotropy. We also performed a reverse MR analysis testing the causal effects of ALS on the above autoimmune traits. RESULTS:After applying Bonferroni correction for multiple testing, our MR analyses showed that the liability to autoimmune disorders does not affect ALS risk. Our reverse MR analysis also did not support the effects of liability to ALS on other autoimmune disorders. The results of the main IVW MR analyses were generally supported by our sensitivity MR analyses. The variance in the exposures explained by the sets of SNPs used as MR instruments ranged from 8.1 × 10 to 0.31. Our MR study was well-powered to detect effects as small as an odds ratio (OR) of 1.045 for ALS in the main MR and as small as an OR of 1.32 in the reverse MR. CONCLUSION:Our MR study does not support a relationship between liability to autoimmune disorders and ALS risk in the European population. The associations observed in epidemiological studies could be partly attributed to shared biology or environmental confounders. 10.1186/s12916-022-02578-9
Shared genetic risk factors and causal association between psoriasis and coronary artery disease. Nature communications Psoriasis and coronary artery disease (CAD) are related comorbidities that are well established, but whether a genetic basis underlies this is not well studied. We apply trans-disease meta-analysis to 11,024 psoriasis and 60,801 CAD cases, along with their associated controls, identifying one opposing and three shared genetic loci, which are confirmed through colocalization analysis. Combining results from Bayesian credible interval analysis with independent information from genomic, epigenomic, and spatial chromatin organization, we prioritize genes (including IFIH1 and IL23A) that have implications for common molecular mechanisms involved in psoriasis and CAD inflammatory signaling. Chronic systemic inflammation has been associated with CAD and myocardial infarction, and Mendelian randomization analysis finds that CAD as an exposure can have a significant causal effect on psoriasis (OR = 1.11; p = 3×10) following adjustment for BMI and waist-hip ratio. Together, these findings suggest that systemic inflammation which causes CAD can increase the risk of psoriasis. 10.1038/s41467-022-34323-4
Lack of causal association between heart failure and osteoporosis: a Mendelian randomization study. BMC medical genomics OBJECTIVES:Heart failure (HF) has been implicated in osteoporosis. However, causality remains unestablished. Here, we sought to assess causal associations of genetic liability to HF with osteoporosis using Mendelian randomization (MR) analyses. METHODS:Independent single nucleotide polymorphisms associated with HF at genome-wide significance were derived from a large genome-wide association study (GWAS) (including up to 977,323 individuals). We obtained summary statistics for forearm (FA) bone mineral density (BMD) (n = 8,143), femoral neck (FN) BMD (n = 32,735), lumbar spine (LS) BMD (n = 28,498), heel (HE) BMD (n = 426,824), and fracture (n = 1,214,434) from other GWAS meta-analyses. Inverse variance weighted (IVW) and several supplementary methods were performed to calculate the MR estimates. RESULTS:Genetically determined HF has no causal effect on FA-BMD (odds ratio (OR) 1.17; 95% confidence interval (CI) 0.82, 1.66; P = 0.389), FN-BMD (OR 1.01; 95% CI 0.85, 1.19; P = 0.936), LS-BMD (OR 0.96; 95% CI 0.80, 1.17; P = 0.705), HE-BMD (OR 1.01; 95% CI 0.90, 1.13; P = 0.884), and fracture risk (OR 1.00; 95% CI 0.92, 1.10; P = 0.927). Complementary analyses returned broadly consistent results. CONCLUSION:This MR study provides genetic evidence that HF may not lead to an increased risk of reduced BMDs or fracture. 10.1186/s12920-022-01385-8
Association of demographic and clinical factors with risk of acute pancreatitis: An exposure-wide Mendelian randomization study. Molecular genetics & genomic medicine BACKGROUND:The incidence of acute pancreatitis (AP) is increasing over years, which brings enormous economy and health burden. However, the aetiologies of AP and underlying mechanisms are still unclear. Here, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations between all reported possible risk factors and AP using publicly available genome-wide association study summary statistics. METHODS:A series of quality control steps were taken in our analysis to select eligible instrumental single nucleotide polymorphisms which were strongly associated with exposures. To make the conclusions more robust and reliable, we utilized several analytical methods (inverse-variance weighting, MR-PRESSO method, weighted median, MR-Egger regression) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, radial regression and leave-one-out sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on each exposure. A two-step MR method was applied to explore mediators in significant associations. RESULTS:Genetic predisposition to cholelithiasis (effect estimate: 17.30, 95% CI: 12.25-22.36, p = 1.95 E-11), body mass index (0.32, 95% CI: 0.13-0.51, p < 0.001), body fat percentage (0.57, 95% CI: 0.31-0.83, p = 1.31 E-05), trunk fat percentage (0.36, 95% CI: 0.14-0.59, p < 0.005), ever smoked (1.61, 95% CI: 0.45-2.77, p = 0.007), and limbs fat percentage (0.55, 95% CI: 0.41-0.69, p < 0.001) were associated with an increased risk of AP. In addition, whole-body fat-free mass (-0.32, 95% CI: -0.55 to -0.10, p = 0.004) was associated with a decrease risk of AP. CONCLUSION:Genetic predisposition to cholelithiasis, obesity and smoking could be causally associated with an increased risk of AP, and whole body fat-free mass could be associated with a decreased risk of AP. 10.1002/mgg3.2091
Diet-derived antioxidants and nonalcoholic fatty liver disease: a Mendelian randomization study. Hepatology international BACKGROUND:Whether supplementation with diet-derived antioxidants is beneficial for nonalcoholic fatty liver disease (NAFLD) is still controversial and we hope to answer this question using population-based genetic data. METHODS:A total of 8485 NAFLD cases and 658,849 healthy controls from four independent NAFLD genome-wide association studies were enrolled in this study. Genetic variants closely associated with the diet-derived antioxidants were selected to predict their circulating levels. A bi-directional Mendelian randomization (MR) design was employed to assess their causations. RESULTS:Genetic correlation analyses suggested inverse associations between diet-derived antioxidants and NAFLD. MR analyses indicated that the odds ratio (OR) of per standard deviation increase in genetically predicted toenail and blood selenium was 1.179 for NAFLD (95% confidence interval [1.083-1.284]). Also, the genetically elevated selenium level was causally associated with increased levels of C-reactive protein, fibrinogen, alkaline phosphatase and glycated hemoglobin. The OR of 1 µg/dL increase in genetically predicted serum lycopene was 1.082 (95%CI [1.051-1.113]). No other causal associations were found for NAFLD. However, we observed protective effects of genetically predicted β-carotene (OR = 0.929[0.911-0.947]) and retinol (OR = 0.483[0.460-0.508]) on type 2 diabetes (T2D), and further they could reduce the serum levels of blood lipids and glucose. Reverse MR analysis suggested genetically predicated NAFLD status would not affect the levels of diet-derived antioxidants. CONCLUSION:Overall, we observed the positive associations of genetically predicted selenium and lycopene with NAFLD. However, the genetically predicted β-carotene and retinol levels were inversely associated with the risk of T2D. 10.1007/s12072-022-10443-3
Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians. International journal of epidemiology BACKGROUND:Whether non-alcoholic fatty liver disease (NAFLD) causes cardiovascular disease (CVD) and type 2 diabetes (T2D) is unclear and possible differences between ethnicities have not been thoroughly explored. We used Mendelian randomization (MR) to assess the role of NAFLD in CVD and T2D risk in Europeans and East Asians. METHODS:We conducted a MR study using genetic predictors of alanine aminotransferase (ALT), liability to NAFLD, aspartate transaminase (AST), liver magnetic resonance imaging corrected T1 and proton density fat fraction and combined them with genome-wide association studies (GWAS) summary statistics of CVD, T2D and glycaemic traits (sample size ranging from 14 400 to 977 320). Inverse-variance weighted analysis was used to assess the effect of NAFLD in these outcomes, with sensitivity analyses and replication in FinnGen. We conducted analyses in East Asians using ethnicity-specific genetic predictors of ALT and AST, and the respective outcome GWAS summary statistics. RESULTS:In Europeans, higher ALT was associated with higher T2D risk (odds ratio: 1.77 per standard deviation, 95% CI 1.5 to 2.08), with similar results for other exposures, across sensitivity analyses and in FinnGen. Although NAFLD proxies were related to higher coronary artery disease (CAD) and stroke risk, sensitivity analyses suggested possible bias by horizontal pleiotropy. In East Asians, higher ALT was possibly associated with higher T2D risk, and ALT and AST were inversely associated with CAD. CONCLUSIONS:NAFLD likely increases the risk of T2D in Europeans and East Asians. Potential differential effects on CAD between Europeans and East Asians require further investigation. 10.1093/ije/dyac212
Genetic liability to bipolar disorder and body mass index: A bidirectional two-sample Mendelian randomization study. Bipolar disorders OBJECTIVES:Bipolar disorder is associated with increased body mass index (BMI), but it remains undetermined if this association is causal and, if so, in which direction it goes. Here, we sought to answer these questions using bidirectional two-sample Mendelian randomization, a method from genetic epidemiology that uses data from genome-wide association studies (GWAS) to examine whether a risk factor is causal for an outcome METHODS: We used summary statistics from GWAS of bipolar disorder and BMI conducted using data collected by the Psychiatric Genomics Consortium and the UK Biobank, respectively. The genetic instrument for bipolar disorder contained 53 SNPs and explained 0.5% of phenotypic variance, while the genetic instrument for BMI contained 517 SNPs and explained 7.1% of phenotypic variance RESULTS: Our findings suggest that genetic liability to bipolar disorder reduces BMI (slope from Egger regression = -0.195, p = 0.004). It follows that a twofold increase in the genetic liability to bipolar disorder leads to a 0.6 (kg/m ) reduction in BMI, predominantly driven by reduced fat mass. Conversely, we found no evidence that BMI causes changes in the risk of developing bipolar disorder CONCLUSION: The results of this study suggest that the increased BMI observed among individuals with bipolar disorder is not a direct consequence of genetic liability to bipolar disorder, but may more likely represent the sum of downstream correlates of manifest bipolar disorder, such as side effects of pharmacological treatment, poor diet, and sedentary lifestyle. As these factors are all modifiable, they can be targeted as part of clinical management. 10.1111/bdi.13267
Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC medicine BACKGROUND:Several recent observational studies have reported that gut microbiota composition is associated with preeclampsia. However, the causal effect of gut microbiota on preeclampsia-eclampsia is unknown. METHODS:A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n=13,266) conducted by the MiBioGen consortium. The summary statistics of preeclampsia-eclampsia were obtained from the FinnGen consortium R7 release data (5731 cases and 160,670 controls). Inverse variance weighted, maximum likelihood, MR-Egger, weighted median, weighted model, MR-PRESSO, and cML-MA were used to examine the causal association between gut microbiota and preeclampsia-eclampsia. Reverse Mendelian randomization analysis was performed on the bacteria that were found to be causally associated with preeclampsia-eclampsia in forward Mendelian randomization analysis. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables. RESULTS:Inverse variance weighted estimates suggested that Bifidobacterium had a protective effect on preeclampsia-eclampsia (odds ratio = 0.76, 95% confidence interval: 0.64-0.89, P = 8.03 × 10). In addition, Collinsella (odds ratio = 0.77, 95% confidence interval: 0.60-0.98, P = 0.03), Enterorhabdus (odds ratio = 0.76, 95% confidence interval: 0.62-0.93, P = 8.76 × 10), Eubacterium (ventriosum group) (odds ratio = 0.76, 95% confidence interval: 0.63-0.91, P = 2.43 × 10), Lachnospiraceae (NK4A136 group) (odds ratio = 0.77, 95% confidence interval: 0.65-0.92, P = 3.77 × 10), and Tyzzerella 3 (odds ratio = 0.85, 95% confidence interval: 0.74-0.97, P = 0.01) presented a suggestive association with preeclampsia-eclampsia. According to the results of reverse MR analysis, no significant causal effect of preeclampsia-eclampsia was found on gut microbiota. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. CONCLUSIONS:This two-sample Mendelian randomization study found that Bifidobacterium was causally associated with preeclampsia-eclampsia. Further randomized controlled trials are needed to clarify the protective effect of probiotics on preeclampsia-eclampsia and their specific protective mechanisms. 10.1186/s12916-022-02657-x
Chickenpox and multiple sclerosis: A Mendelian randomization study. Journal of medical virology Observational studies have suggested a suspected association between varicella-zoster virus (VZV) infection and multiple sclerosis (MS), but the connection has remained unclear. The aim of the present study is to evaluate the causal relationship between chickenpox which is caused by VZV infection and MS. We performed a two-sample Mendelian randomization analysis to investigate the association of chickenpox with MS using summary statistics from genome-wide association studies (GWAS). The GWAS summary statistics data for chickenpox was from the 23andMe cohort including 107 769 cases and 15 982 controls. A large summary of statistical data from the International Multiple Sclerosis Genetics Consortium (IMSGC) was used as the outcome GWAS data set, including 14 802 MS cases and 26 703 controls. We found evidence of a significant association between genetically predicted chickenpox and risk of MS (odds ratio [OR] = 35.27, 95% confidence interval [CI] = 22.97-54.17, p = 1.46E-59). Our findings provided evidence indicating a causal effect of chickenpox on MS. Further elucidations of this association and underlying mechanisms are needed for identifying feasible interventions to promote MS prevention. 10.1002/jmv.28315
Relationship between lipids and sleep apnea: Mendelian randomization analysis. World journal of clinical cases BACKGROUND:Lipids increase the risk of sleep apnea; however, the causality between them is still inconclusive. AIM:To explore the causal relationship between serum lipids and sleep apnea using two-sample Mendelian randomization (MR) analysis. METHODS:Single nucleotide polymorphism (SNP) data related to serum lipids were obtained from the Global Lipids Genetics Consortium study, which included 188578 individuals of European ancestry. Additionally, sleep apnea-related SNP data were collected from the United Kingdom Biobank study, which comprised 463005 individuals of European ancestry. Two-sample MR analysis was performed to assess the causality between serum lipids and sleep apnea based on the above public data. RESULTS:Genetically predicted low-density lipoprotein (odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.99 to 1.00; = 0.58), high-density lipoprotein (OR = 0.99, 95%CI = 0.99 to 1.00; = 0.91), triglyceride (OR = 1.00, 95%CI = 0.99 to 1.00; = 0.92), and total cholesterol (OR = 0.99, 95%CI = 0.99 to 1.00; = 0.33) were causally unrelated to sleep apnea. CONCLUSION:Our MR analysis suggests that genetically predicted serum lipids are not risk factors of sleep apnea. 10.12998/wjcc.v10.i31.11403
Causal association between heart failure and bone mineral density: Insights from a two-sample bidirectional Mendelian randomization study. Genomics In recent times, the association between HF and BMD has attracted enormous interest in the scientific community. However, published epidemiological observational studies on the relationship between HF and BMD remain inconclusive. Herein, we evaluated from the analytical perspective a two-sample bidirectional MR study to analyze the causal association between HF and BMD using a summary-level GWAS Catalog. To select instrumental SNPs strongly associated with exposure, we took a series of rigorous quality control steps at the time of analysis. The causal MR assessment of HF on the risk of BMD was performed first and then in the opposite direction. To make the conclusions more reliable and robust, the fixed-effects IVW, weighted median-based method, MR-Egger, simple mode and weighted mode were utilized. A maximum likelihood model was also used if necessary. MR-Egger regression, IVW "leave-one-out" sensitivity analysis, MR-PRESSO, MR-Egger intercept test and Cochran's Q statistic methods were used to assess heterogeneity and pleiotropy. Our MR studies supported a meaningful causal association between HF and TB-BMD (IVW: OR = 0.78, 95% CI: 0.68-0.87, p = 0.00588). At the same time, we did not find a significant causal relationship between HF and FA-BMD, FN-BMD or LS-BMD. No significant causal relationships between BMD and HF were observed. This bidirectional MR analysis suggested a causal association of HF with only low TB-BMD, while the reverse causality hypothesis was not found. Studies of the prevention and treatment of total bone mineral density decline in patients with heart failure need to be performed. 10.1016/j.ygeno.2022.110522
Acute pancreatitis in COVID-19 patients: true risk? Bulthuis Margo C,Boxhoorn Lotte,Beudel Martijn,Elbers Paul W G,Kop Marnix P M,van Wanrooij Roy L J,Besselink Marc G,Voermans Rogier P Scandinavian journal of gastroenterology BACKGROUND:A relation between coronavirus disease 2019 (COVID-19) and acute pancreatitis has been suggested. However, the incidence and clinical relevance of this relation remain unclear. OBJECTIVE:We aimed to investigate the incidence, severity and clinical impact of acute pancreatitis in patients with COVID-19. METHODS:This is a cross-sectional study of a prospective, observational cohort concerning all COVID-19 patients admitted to two Dutch university hospitals between 4 March 2020 and 26 May 2020. Primary outcome was acute pancreatitis potentially related to COVD-19 infection. Acute pancreatitis was defined according to the revised Atlanta Classification. Potential relation with COVID-19 was defined as the absence of a clear aetiology of acute pancreatitis. RESULTS:Among 433 patients with COVID-19, five (1.2%) had potentially related acute pancreatitis according to the revised Atlanta Classification. These five patients suffered from severe COVID-19 infection; all had (multiple) organ failure and 60% died. None of the patients developed necrotizing pancreatitis. Moreover, development of acute pancreatitis did not lead to major treatment consequences. CONCLUSIONS:In contrast with previous research, our study demonstrated that COVID-19 related acute pancreatitis is rare and of little clinical impact. It is therefore debatable if acute pancreatitis in COVID-19 patients requires specific screening. We hypothesize that acute pancreatitis occurs in patients with severe illness due to COVID-19 infection as a result of transient hypoperfusion and pancreatic ischemia, not as a direct result of the virus. 10.1080/00365521.2021.1896776
Persistent Cannabis Abuse and Risk for Hospitalization for Acute Pancreatitis: A Cross-Sectional Study in United States Hospitals. Bhandari Renu,Gupta Siddharth,Modi Karnav,Raval Maharshi R,Joundi Hajara,Patel Jeet R,Pannu Amanpreet K,Sharma Prerna Cureus Objectives To explore the independent association between cannabis abuse and subsequent hospitalizations for acute pancreatitis (AP) and delineate the demographic differences among AP in patients with and without persistent cannabis abuse. Methods We conducted a retrospective cross-sectional study using the nationwide inpatient sample and included 50,444,133 patients (age 18-50 years) with a primary discharge diagnosis for medical illnesses and further grouped by presence of AP (N = 666,248). We used the logistic regression model to measure the odds ratio (OR) of the association between cannabis abuse and hospitalization for AP and adjusted it for demographic confounders and comorbid risk factors. Results Cannabis abuse significantly increases the odds for AP-related hospitalization (OR 2.12, P <0.001). When the regression model was controlled for potential risk factors (gall stones, cystic fibrosis, hypertriglyceridemia, hypercalcemia, hyperparathyroidism, abdominal surgeries, tobacco abuse, and alcohol abuse), cannabis abuse did not increase the odds for AP-related hospitalization (OR 0.72, P <0.001) due to the significant effect caused by gallstones (OR 30.98, P <0.001) and alcohol abuse (OR 12.69, P <0.001). AP inpatients with cannabis abuse were younger compared to non-cannabis abusers (mean age, 35.7 vs. 37.9 years), and majorly male (70.9% vs. 53.8%). AP was considerably more prevalent in whites (60.6%), followed by blacks (18.3%) and Hispanics (15.2%). Conclusion Cannabis abuse increased the unadjusted odds for AP-related hospitalization by two times, but after controlling for potential risk factors the adjusted odds of association significantly reduced. Cannabis-induced AP can be treated if a problematic recreational cannabis use pattern is discontinued at an earlier stage. Therefore, awareness campaigns and early supportive therapy among cannabis abusers might help diagnose and treat the comorbidity and improve the quality of life. 10.7759/cureus.15601
The Risk of Acute and Chronic Pancreatitis in Celiac Disease. Alkhayyat Motasem,Saleh Mohannad Abou,Abureesh Mohammad,Khoudari George,Qapaja Thabet,Mansoor Emad,Simons-Linares C Roberto,Vargo John,Stevens Tyler,Rubio-Tapia Alberto,Chahal Prabhleen Digestive diseases and sciences BACKGROUND AND AIMS:Celiac disease (CD) is a chronic immune-mediated enteropathy that is precipitated by dietary gluten in genetically predisposed individuals. A few studies reported a higher incidence of pancreatitis in the CD population. Using a large US database, we sought to describe the epidemiology, risk, and outcomes of acute pancreatitis (AP) and chronic pancreatitis (CP) in CD patients. METHODS:We queried a multiple health system data analytics and research platform (Explorys Inc, Cleveland, OH, USA). A cohort of patients with a diagnosis of CD was identified. Subsequently, individuals who developed a new diagnosis of AP and CP after at least 30 days of being diagnosed with CD were identified. A multivariate regression model was performed to adjust for multiple confounding factors. RESULTS:Of the 72,965,940 individuals in the database, 133,400 (0.18%), 362,050 (0.50%), and 95,190 (0.13%) had CD, AP, and CP, respectively. New diagnosis of AP and CP after at least 30 days of CD diagnosis was 1.06%, 0.52%, respectively, compared to non-CD patients with 0.49% for AP and 0.13% for CP, P < .0001. In multivariate regression analysis, patients with CD were at higher risk of developing AP [OR 2.66; 95% CI 2.55-2.77] and CP [OR 2.18; 95% CI 2.04-2.34]. Idiopathic AP was the most common etiology among CD patients [OR 1.54; 95% CI 1.34-1.77]. CONCLUSIONS:In this largest US population database and after adjusting for several confounders, patients with CD were at increased risk of developing AP and CP. Celiac disease patients had worse outcomes and higher medical burden compared to non-CD patients. Recurrent abdominal pain that suggests pancreatic etiology, idiopathic pancreatitis, or elevation of pancreatic enzymes should warrant investigation for CD as a potential cause of pancreatic disease. 10.1007/s10620-020-06546-2
Risk of acute atherosclerotic cardiovascular disease in patients with acute and chronic pancreatitis. Sung Li-Chin,Chang Chuen-Chau,Lin Chao-Shun,Yeh Chun-Chieh,Cherng Yih-Giun,Chen Ta-Liang,Liao Chien-Chang Scientific reports The association between pancreatitis and acute myocardial infarction or stroke remains incompletely understood. This study aimed to evaluate the long-term risk of acute atherosclerotic cardiovascular disease (ASCVD) in people with acute and chronic pancreatitis. Using research database of Taiwan's National Health Insurance, we identified 2678 patients aged ≥ 20 years with newly diagnosed pancreatitis in 2000-2008. A cohort of 10,825 adults without pancreatitis was selected for comparison, with matching by age and sex. Both cohorts were followed from 2000 to the end of 2013, and incident acute ASCVD was identified during the follow-up period. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acute ASCVD associated with pancreatitis were calculated. Compared with the comparison cohort, the adjusted HR of acute ASCVD were 1.76 (95% CI 1.47-2.12) and 3.42 (95% CI 1.69-6.94) for people with acute pancreatitis and chronic pancreatitis, respectively. A history of alcohol-related illness (HR 9.49, 95% CI 3.78-23.8), liver cirrhosis (HR 7.31, 95% CI 1.81-29.5), and diabetes (HR 6.89, 95% CI 2.18-21.8) may worsen the risk of acute ASCVD in patients with chronic pancreatitis. Compared with people had no pancreatitis, patients with acute pancreatitis who had alcohol-related illness (HR 4.66, 95% CI 3.24-6.70), liver cirrhosis (HR 4.44, 95% CI 3.05-6.47), and diabetes (HR 2.61, 95% CI 2.03-3.36) were at increased risk of acute ASCVD. However, the cumulative use of metformin was associated with a reduced risk of acute ASCVD in the acute pancreatitis cohort (HR 0.30, 95% CI 0.17-0.50). Compared with the control group, patients with acute or chronic pancreatitis were more likely to have an increased risk of acute ASCVD, while the use of metformin reduced the risk of acute ASCVD. Our findings warrant a survey and education on acute ASCVD for patients with acute and chronic pancreatitis. 10.1038/s41598-021-99915-4
Risk factors for new-onset diabetes mellitus following acute pancreatitis: a prospective study. European review for medical and pharmacological sciences OBJECTIVE:Acute pancreatitis (AP) is increasingly recognized as a major cause of diabetes, however, the frequency and risk factors associated with new-onset diabetes are not well established. We aimed to assess the frequency and risk factors associated with new-onset diabetes, the time of diabetes occurrence, and the difference between early and late-onset diabetes following an AP episode. PATIENTS AND METHODS:This prospective study included adult patients with AP admitted to a tertiary referral center, followed-up for one year to assess the occurrence of postpancreatitis diabetes. Diabetes was defined in accordance with World Health Organization criteria and the severity of AP was assessed based on the 2012 revised Atlanta classification. RESULTS:Of 329 patients with AP, 29 (8.8%) were diagnosed with diabetes secondary to AP. Of these, 21 (6.37%) had early-onset diabetes (within one month after the acute episode) whereas 8 (2.42%) had late-onset diabetes (more than one month after the AP episode). Obesity and acute necrosis were more frequent in patients with new-onset diabetes compared to those without (55.2% vs. 33.4%, p=0.040 and 31% vs. 7.7%, p<0.01), and remained statistically significant in multivariate analysis. No statistically significant differences were found between these groups regarding sex, age, etiology and severity of AP. The patients with early-onset diabetes were older than those with late-onset (61 vs. 45 years old), in univariate and multivariate analysis (p=0.018 and p=0.038, OR=0.87). CONCLUSIONS:Less than 10% of patients with AP developed diabetes within 1 year, particularly obese patients and those with acute pancreatic necrosis of more than 50%. Patients aged over 61 years old developed diabetes in the first month after the acute episode of AP. 10.26355/eurrev_202208_29511
Genetic effects of iron levels on liver injury and risk of liver diseases: A two-sample Mendelian randomization analysis. Frontiers in nutrition Background and aims:Although iron homeostasis has been associated with liver function in many observational studies, the causality in this relationship remains unclear. By using Mendelian Randomization analyses, we aimed to evaluate the genetic effects of increased systemic iron levels on the risk of liver injury and various liver diseases. Moreover, in light of the sex-dependent iron regulation in human beings, we further estimated the sex-specific effect of iron levels in liver diseases. Methods:Independent single nucleotide polymorphisms associated with systemic iron status (including four indicators) at the genome-wide significance level from the Genetics of Iron Status (GIS) Consortium were selected as instrumental variables. Summary data for six liver function biomarkers and five liver diseases were obtained from the UK Biobank, the Estonian Biobank, the eMERGE network, and FinnGen consortium. Mendelian Randomization assessment of the effect of iron on liver function and liver diseases was conducted. Results:Genetically predicted iron levels were positively and significantly associated with an increased risk of different dimensions of liver injury. Furthermore, increased iron status posed hazardous effects on non-alcoholic fatty liver disease, alcoholic liver disease, and liver fibrosis/cirrhosis. Sex-stratified analyses indicated that the hepatoxic role of iron might exist in NAFLD and liver fibrosis/cirrhosis development among men. No significantly causal relationship was found between iron status and viral hepatitis. Conclusion:Our study adds to current knowledge on the genetic role of iron in the risk of liver injury and related liver diseases, which provides clinical and public health implications for liver disease prevention as iron status can be modified. 10.3389/fnut.2022.964163
A Mendelian randomization study of genetic predisposition to autoimmune diseases and COVID-19. Scientific reports Autoimmune diseases and coronavirus disease 2019 (COVID-19) share many similarities. Concerns have arisen that autoimmune diseases may increase the susceptibility and severity of COVID-19. We used Mendelian randomization to investigate whether liability to autoimmune diseases is related to COVID-19 susceptibility and severity. Genetic instruments for 8 autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis and juvenile idiopathic arthritis, were obtained from published genome-wide association studies. Two-sample Mendelian randomization analyses of the associations of liability to each autoimmune disease with COVID-19 infection, hospitalized COVID-19, and very severe COVID-19 were performed using the latest publicly available genome-wide association study for COVID-19. Genetic liability to each of the autoimmune diseases was largely not associated with COVID-19 infection, hospitalized COVID-19, or very severe COVID-19 after accounting for multiple comparison. Sensitivity analysis excluding genetic variants in the human leukocyte antigen gene, which has an important role in the immune response, showed similar results. The autoimmune diseases examined were largely not genetically associated with the susceptibility or severity of COVID-19. Further investigations are warranted. 10.1038/s41598-022-22711-1
Hypothyroidism has a protective causal association with hepatocellular carcinoma: A two-sample Mendelian randomization study. Frontiers in endocrinology Objective:Observational studies suggest an association between hypothyroidism and the risk of hepatocellular carcinoma (HCC), but the causality and direction of these effects are still inconclusive. We aim to test whether hypothyroidism is causally associated with the risk of HCC by using Mendelian randomization (MR) analysis. Methods:Single-nucleotide polymorphisms (SNPs) associated with hypothyroidism were screened a genome-wide association study (GWAS) on 337,159 individuals of European descent (16,376 cases and 320,783 controls). The SNPs associated with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were selected from a GWAS of 72,167 individuals of European descent. Summary-level data for HCC (168 cases and 372,016 controls) were extracted from UK Biobank. An inverse-variance-weighted (IVW) method was used as the primary MR analysis. Sensitivity analyses were examined MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. The assumption that exposure causes outcome was verified using the MR Steiger test. Results:Two-Sample MR analysis showed inverse associations between genetically predicted hypothyroidism and HCC risk (OR = 0.997, 95% CI, 0.995-0.999; = 0.016). There were no statistical indications of heterogeneity among instruments (-het = 0.667). Across five MR methods, genetically predicted hypothyroidism shows a consistent correlation with HCC. The leave-one-out analysis indicated that no single SNP changed the overall estimate ( = 0.016). In addition, the MR Steiger test revealed that hypothyroidism was causal for HCC and not the opposite ( = 0.000). Finally, there was no evidence for a direct causal effect of TSH level and FT4 level on HCC risk. Conclusion:Our results provide some that genetically determined hypothyroidism decreases the risk of HCC, although the size of the causal estimate is small. Further research is required to comprehend the mechanisms underlying this putative causative association, and follow-up clinical trials need to be conducted to establish whether inducing hypothyroidism could be beneficial for patients who are suffering from HCC. During future treatment of hypothyroidism, close attention to liver function may also be required to prevent a possible increased risk of HCC. 10.3389/fendo.2022.987401
Genetic susceptibility to COVID-19 may increase the risk of erectile dysfunction: A two-sample Mendelian randomization study. Andrologia Coronavirus disease 19 (COVID-19) and erectile dysfunction (ED) have been linked in some observational research, but the causality of this association in the European population is uncertain. Therefore, the research intended to investigate the causality of susceptibility to COVID-19 on ED. We used Mendelian randomization (MR) analysis for this research. The subjects were from two genome-wide association studies (GWAS) of the European population, including COVID-19 (14,134 cases and 1,284,876 controls) and ED (6175 cases and 217,630 controls). We utilized the inverse variance-weighted (IVW) to evaluate the causality of COVID-19 genetic susceptibility on ED. Heterogeneity and pleiotropy were determined using the Cochran's Q test and MR-Egger regression. The robustness of the findings was verified using the Leave-one-out method. We obtained six single nucleotide polymorphisms (SNPs) as COVID-19 genetic instrumental variables (IVs), and there was no significant pleiotropy, heterogeneity or bias in these IVs. MR analysis revealed the causality of genetic susceptibility to COVID-19 on elevated risk of ED (OR  = 1.235, 95% CI: 1.044-1.462, p < 0.05). The present study suggested the causality of genetic susceptibility to COVID-19 on elevated ED risk among the European population. Therefore, in order to decrease the ED risk, the European population ought to positively prevent COVID-19. 10.1111/and.14527
Smoking, alcohol and coffee consumption and risk of low back pain: a Mendelian randomization study. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society PURPOSE:Low back pain (LBP) is a common health problem in the global population. This study aims to assess whether smoking initiation, alcohol consumption, and coffee consumption are causally with an increased risk of LBP. METHODS:A two-sample Mendelian Randomization (MR) study was designed, based on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with genome-wide significance level (P < 5.0 × 10) were selected as instrumental variables for each exposure. Standard inverse-variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods, which relax some IV assumptions, were used for sensitivity analysis. RESULTS:Genetically predicted smoking initiation was causally associated with higher odds of LBP. The pooled OR of LBP using IVW method was 1.36 (95%CI 1.22 1.52; P = 6.0 × 10) for one SD increase in the prevalence of smoking initiation, which was supported by the weighted median method (OR: 1.41, 95%CI 1.22, 1.64; P = 5.7 × 10). Sensitivity analysis confirmed the robustness of pooled OR of LBP. There was no evidence to suggest a causal effect of alcohol and coffee consumption on LBP. The pooled ORs of LBP were 1.36 (95%CI 0.94, 1.97; P = 0.10) for alcohol consumption and 1.00 (95%CI 0.99, 1.00; P = 0.17) for coffee consumption, respectively. CONCLUSION:Smoking is casually associated with an increased risk of LBP. Smoking control should be recommended in LBP patients to avoid worsening the disease. The safety of LBP with moderate alcohol and coffee consumption merits more study. 10.1007/s00586-022-07389-3