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    An Atlas of Genetic Correlations and Genetically Informed Associations Linking Psychiatric and Immune-Related Phenotypes. JAMA psychiatry Importance:Certain psychiatric and immune-related disorders are reciprocal risk factors. However, the nature of these associations is unclear. Objective:To characterize the pleiotropy between psychiatric and immune-related traits, as well as risk factors of hypothesized relevance. Design, Setting, and Participants:This genetic association study was conducted from July 10, 2020, to January 15, 2022. Analyses used genome-wide association (GWA) statistics related to 14 psychiatric traits; 13 immune-related phenotypes, ie, allergic, autoimmune, and inflammatory disorders; and 15 risk factors related to health-related behaviors, social determinants of health, and stress response. Genetically correlated psychiatric-immune pairs were assessed using 2-sample mendelian randomization (MR) with sensitivity analyses and multivariable adjustment for genetic associations of third variables. False discovery rate correction (Q value < .05) was applied for each analysis. Exposures:Genetic associations. Main Outcomes and Measures:Genetic correlations and MR association estimates with SEs and P values. A data-driven approach was used that did not test a priori planned hypotheses. Results:A total of 44 genetically correlated psychiatric-immune pairs were identified, including 31 positive correlations (most consistently involving asthma, Crohn disease, hypothyroidism, and ulcerative colitis) and 13 negative correlations (most consistently involving allergic rhinitis and type 1 diabetes). Correlations with third variables were especially strong for psychiatric phenotypes. MR identified 7 associations of psychiatric phenotypes on immune-related phenotypes that were robust to multivariable adjustment, including the positive association of (1) the psychiatric cross-disorder phenotype with asthma (odds ratio [OR], 1.04; 95% CI, 1.02-1.06), Crohn disease (OR, 1.09; 95% CI, 1.05-1.14), and ulcerative colitis (OR, 1.09; 95% CI, 1.05-1.14); (2) major depression with asthma (OR, 1.25; 95% CI, 1.13-1.37); (3) schizophrenia with Crohn disease (OR, 1.12; 95% CI, 1.05-1.18) and ulcerative colitis (OR, 1.14; 95% CI, 1.07-1.21); and a negative association of risk tolerance with allergic rhinitis (OR, 0.77; 95% CI, 0.67-0.92). Conclusions and Relevance:Results of this genetic association study suggest that genetic liability for psychiatric disorders was associated with liability for several immune disorders, suggesting that vertical pleiotropy related to behavioral traits (or correlated third variables) contributes to clinical associations observed in population-scale data. 10.1001/jamapsychiatry.2022.0914
    Association of Chronic Kidney Disease With Risk of Intracerebral Hemorrhage. JAMA neurology Importance:The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases. Objective:To determine whether there is an association between CKD and ICH risk. Design, Setting, and Participants:A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022. Exposures:CKD stages 1 to 5. Main Outcomes and Measures:The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes. Results:In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P < .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007). Conclusions and Relevance:In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association. 10.1001/jamaneurol.2022.2299
    Causal Effects of Positive Affect, Life Satisfaction, Depressive Symptoms, and Neuroticism on Kidney Function: A Mendelian Randomization Study. Journal of the American Society of Nephrology : JASN BACKGROUND:Further investigation of the causal effects of psychologic wellbeing on kidney function is warranted. METHODS:In this Mendelian randomization (MR) study, genetic instruments for positive affect, life satisfaction, depressive symptoms, and neuroticism were introduced from a previous genome-wide association study meta-analysis of European individuals. Summary-level MR was performed using the CKDGen data of European ancestry (=567,460), and additional allele score-based MR was performed in the individual-level data of White British UK Biobank participants (=321,024). RESULTS:In summary-level MR with the CKDGen data, depressive symptoms were a significant causative factor for kidney function impairment (CKD OR, 1.45; 95% confidence interval, 1.07 to 1.96; eGFR change [%] beta -2.18; 95% confidence interval, -3.61 to -0.72) and pleiotropy-robust sensitivity analysis results supported the causal estimates. A genetic predisposition for positive affect was significantly associated with better kidney function (CKD OR, 0.69; 95% confidence interval, 0.52 to 0.91), eGFR change [%] beta 1.50; 95% confidence interval, 0.09 to 2.93) and sensitivity MR analysis results supported the finding for CKD outcome, but was nonsignificant for eGFR. Life satisfaction and neuroticism exposures showed nonsignificant causal estimates. In the UK Biobank with covariate-adjusted allele score MR analysis, allele scores for positive affect and life satisfaction were causally associated with reduced risk of CKD and higher eGFR. In contrast, neuroticism allele score was associated with increased risk of CKD and lower eGFR, and depressive symptoms allele score was associated with lower eGFR, but showed nonsignificant association with CKD. CONCLUSIONS:Health care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function. 10.1681/ASN.2020071086
    Association between circulating vitamin E and ten common cancers: evidence from large-scale Mendelian randomization analysis and a longitudinal cohort study. BMC medicine BACKGROUND:The association between vitamin E and cancer risk has been widely investigated by observational studies, but the findings remain inconclusive. Here, we aimed to evaluate the causal effect of circulating vitamin E on the risk of ten common cancers, including bladder, breast, colorectal, esophagus, lung, oral and pharynx, ovarian, pancreatic, prostate, and kidney cancer. METHODS:A Mendelian randomization (MR) analytic framework was applied to data from a cancer-specific genome-wide association study (GWAS) comprising a total of 297,699 cancer cases and 304,736 controls of European ancestry. Three genetic instrumental variables associated with circulating vitamin E were selected. Summary statistic-based methods of inverse variance weighting (IVW) and likelihood-based approach, as well as the individual genotyping-based method of genetic risk score (GRS) were used. Multivariable IVW analysis was further performed to control for potential confounding effects. Furthermore, the UK Biobank cohort was used as external validation, supporting 355,543 European participants (incident cases ranged from 437 for ovarian cancer to 4882 for prostate cancer) for GRS-based estimation of circulating vitamin E, accompanied by a one-sample MR analysis of dietary vitamin E intake underlying the time-to-event analytic framework. RESULTS:Specific to cancer GWAS, we found that circulating vitamin E was significantly associated with increased bladder cancer risk (odds ratios [OR] = 6.23, P = 3.05×10) but decreased breast cancer risk (OR = 0.68, P = 8.19×10); however, the significance of breast cancer was dampened (P > 0.05) in the subsequent multivariable MR analysis. In the validation stage of the UK Biobank cohort, we did not replicate convincing causal effects of genetically predicted circulating vitamin E concentrations and dietary vitamin E intake on the risk of ten cancers. CONCLUSIONS:This large-scale population study upon data from cancer-specific GWAS and a longitudinal biobank cohort indicates plausible non-causal associations between circulating vitamin E and ten common cancers in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations. 10.1186/s12916-022-02366-5
    Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study. Journal of the American College of Cardiology BACKGROUND:Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD. OBJECTIVES:This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD. METHODS:Measured and genetically predicted Lp(a) levels were tested for association with 20,432 cases of incident AF in the UK Biobank (N = 435,579). Mendelian randomization analyses were performed by using summary-level data for AF from publicly available genome-wide association studies (N = 1,145,375). RESULTS:In the UK Biobank, each 50 nmol/L (23 mg/dL) increase in Lp(a) was associated with an increased risk of incident AF using measured Lp(a) (HR: 1.03; 95% CI: 1.02-1.04 ; P = 1.65 × 10) and genetically predicted Lp(a) (OR: 1.03; 95% CI: 1.02-1.05; P = 1.33 × 10). Mendelian randomization analyses using independent data replicated the effect (OR: 1.04 per 50 nmol/L Lp[a] increase; 95% CI: 1.03-1.05 per 50 nmol/L Lp[a] increase; P = 9.23 × 10). There was no evidence of risk-conferring effect from low-density lipoprotein cholesterol or triglycerides, and only 39% (95% CI: 27%-73%) of Lp(a) risk was mediated through ASCVD, suggesting that Lp(a) partly influences AF independent of its known effects on ASCVD. CONCLUSIONS:Our findings implicate Lp(a) as a potential causal mediator in the development of AF which show that the effects of Lp(a) extend across myocardial tissues. Ongoing clinical trials for Lp(a)-lowering therapies should evaluate effects on AF prevention. 10.1016/j.jacc.2022.02.018
    Obesity, Type 2 Diabetes, Lifestyle Factors, and Risk of Gallstone Disease: A Mendelian Randomization Investigation. Yuan Shuai,Gill Dipender,Giovannucci Edward L,Larsson Susanna C Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Obesity, type 2 diabetes, and lifestyle factors (cigarette smoking, alcohol drinking, and coffee consumption) have been associated with the risk of developing gallstone disease in observational studies, but whether these associations are causal is undetermined. We conducted a Mendelian randomization study to assess these associations. METHODS:Genetic instruments associated with the exposures at the genome-wide significance (p < 5×10) level were selected from corresponding genome-wide association studies (n=224 459 to 1 232 091 individuals). Summary-level data for gallstone disease were obtained from the UK Biobank (10 520 cases and 350 674 non-cases) and FinnGen consortium (11 675 cases and 121 348 non-cases). Univariable and multivariable Mendelian randomization analyses were conducted. Results from UK Biobank and FinnGen were combined using fixed-effects meta-analysis. RESULTS:The odds ratios were 1.63 (95% confidence interval (CI), 1.49, 1.79) for one standard deviation (SD) increase in body mass index, 1.81 (95% CI, 1.60, 2.05) for one SD increase in waist circumference, 1.13 (95% CI, 1.09, 1.17) for one unit increase in the log-odds ratio of type 2 diabetes and 1.25 (95% CI, 1.16, 1.34) for one SD increase in prevalence of smoking initiation. The associations for body mass index and type 2 diabetes persisted after mutual adjustment. Genetically predicted coffee consumption was inversely associated with gallstone disease after adjustment for body mass index and smoking (odds ratio per 50% increase 0.44, 95% CI, 0.21, 0.91). There was no association with alcohol consumption. CONCLUSIONS:This study supports independent causal roles of obesity, type 2 diabetes, and smoking in gallstone disease. 10.1016/j.cgh.2020.12.034
    ExPheWas: a platform for cis-Mendelian randomization and gene-based association scans. Nucleic acids research Establishing the relationship between protein-coding genes and phenotypes has the potential to inform on the molecular etiology of diseases. Here, we describe ExPheWas (exphewas.ca), a gene-based phenome-wide association study browser and platform that enables the conduct of gene-based Mendelian randomization. The ExPheWas data repository includes sex-stratified and sex-combined gene-based association results from 26 616 genes with 1746 phenotypes measured in up to 413 133 individuals from the UK Biobank. Interactive visualizations are provided through a browser to facilitate data exploration supported by false discovery rate control, and it includes tools for enrichment analysis. The interactive Mendelian randomization module in ExPheWas allows the estimation of causal effects of a genetically predicted exposure on an outcome by using genetic variation in a single gene as the instrumental variable. 10.1093/nar/gkac289
    Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study. Li Xue,Meng Xiangrui,He Yazhou,Spiliopoulou Athina,Timofeeva Maria,Wei Wei-Qi,Gifford Aliya,Yang Tian,Varley Tim,Tzoulaki Ioanna,Joshi Peter,Denny Joshua C,Mckeigue Paul,Campbell Harry,Theodoratou Evropi PLoS medicine BACKGROUND:The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance. METHODS AND FINDINGS:A phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization. CONCLUSION:In this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities. 10.1371/journal.pmed.1002937
    Genetic susceptibility, elevated blood pressure, and risk of atrial fibrillation: a Mendelian randomization study. Genome medicine BACKGROUND:Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. METHODS:First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. RESULTS:The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. CONCLUSIONS:The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF. 10.1186/s13073-021-00849-3
    The Impact of Glycated Hemoglobin (HbA) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank. Au Yeung Shiu Lun,Luo Shan,Schooling C Mary Diabetes care OBJECTIVE:Glycated hemoglobin (HbA) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA with CVD and its subtypes in the UK Biobank using Mendelian randomization. RESEARCH DESIGN AND METHODS:We used 38 genetic variants strongly and independently related to HbA ( = 123,665) applied to the UK Biobank ( = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA with CVD, coronary artery disease (CAD), and stroke (overall and stroke subtypes). Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median, and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 1000 Genomes-based genome-wide association study ( = 184,305) as a validation for CAD. RESULTS:In the UK Biobank, HbA was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83-1.48). However, HbA was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08-2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55-3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03-2.26). The association of HbA with stroke and its subtypes was less clear given the low number of cases. CONCLUSIONS:HbA likely causes CAD. The underlying mechanisms remain to be elucidated. 10.2337/dc18-0289
    Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study. European heart journal AIMS:The causal role of adiposity for several cardiovascular diseases (CVDs) is unclear. Our primary aim was to apply the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 CVDs and arterial hypertension. We also assessed the roles of fat mass and fat-free mass on the same outcomes. METHODS AND RESULTS:Single-nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instrumental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was significantly positively associated with eight outcomes, including and with decreasing magnitude of association: aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio (OR) per 1 kg/m2 increase in BMI ranged from 1.06 [95% confidence interval (CI) 1.02-1.11; P = 2.6 × 10-3] for pulmonary embolism to 1.13 (95% CI 1.05-1.21; P = 1.2 × 10-3) for aortic valve stenosis. There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes (P < 0.05). The strongest magnitude of association was with aortic valve stenosis (OR per 1 kg/m2 increase in fat mass index 1.46, 95% CI 1.13-1.88; P = 3.9 × 10-3). There was suggestive evidence of inverse associations of fat-free mass index with atrial fibrillation, ischaemic stroke, and abdominal aortic aneurysm. CONCLUSION:This study provides evidence that higher BMI and particularly fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions. 10.1093/eurheartj/ehz388
    Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank. Harrison Sean,Davies Neil M,Howe Laura D,Hughes Amanda Science advances Men with more advantaged socioeconomic position (SEP) have been observed to have higher levels of testosterone. It is unclear whether these associations arise because testosterone has a causal impact on SEP. In 306,248 participants of UK Biobank, we performed sex-stratified genome-wide association analysis to identify genetic variants associated with testosterone. Using the identified variants, we performed Mendelian randomization analysis of the influence of testosterone on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and body mass index; and on risk-taking behavior. We found little evidence that testosterone affected socioeconomic position, health, or risk-taking. Our results therefore suggest that it is unlikely that testosterone meaningfully affects these outcomes in men or women. Differences between Mendelian randomization and multivariable-adjusted estimates suggest that previously reported associations with socioeconomic position and health may be due to residual confounding or reverse causation. 10.1126/sciadv.abf8257
    Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank. European heart journal AIMS:Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs. METHODS AND RESULTS:Genetic variants associated with continuous, short (≤6 h) and long (≥9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P < 0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P < 0.001), and suggestive evidence for atrial fibrillation (P < 0.05). However, genetically predicted long sleep duration was not associated with any CVD. CONCLUSION:This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long sleep duration is unlikely to be a causal risk factor for most CVDs. 10.1093/eurheartj/ehab170
    Lipoprotein(a) and Incident Atrial Fibrillation: Leveraging Nature's Randomization to Identify Novel Causal Associations. Journal of the American College of Cardiology 10.1016/j.jacc.2022.02.026
    Smoking, alcohol consumption, and cancer: A mendelian randomisation study in UK Biobank and international genetic consortia participants. Larsson Susanna C,Carter Paul,Kar Siddhartha,Vithayathil Mathew,Mason Amy M,Michaëlsson Karl,Burgess Stephen PLoS medicine BACKGROUND:Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. METHODS AND FINDINGS:We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. CONCLUSIONS:Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk. 10.1371/journal.pmed.1003178
    Mendelian randomization analysis using mixture models for robust and efficient estimation of causal effects. Qi Guanghao,Chatterjee Nilanjan Nature communications Mendelian randomization (MR) has emerged as a major tool for the investigation of causal relationship among traits, utilizing results from large-scale genome-wide association studies. Bias due to horizontal pleiotropy, however, remains a major concern. We propose a novel approach for robust and efficient MR analysis using large number of genetic instruments, based on a novel spike-detection algorithm under a normal-mixture model for underlying effect-size distributions. Simulations show that the new method, MRMix, provides nearly unbiased or/and less biased estimates of causal effects compared to alternative methods and can achieve higher efficiency than comparably robust estimators. Application of MRMix to publicly available datasets leads to notable observations, including identification of causal effects of BMI and age-at-menarche on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI on the risk of major depressive disorder. 10.1038/s41467-019-09432-2
    Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders: A Mendelian Randomization Study. JAMA psychiatry Importance:Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction in a range of neuropsychiatric disorders. Objective:To investigate the relationship between inflammation and changes in brain structures in vivo and to explore a transcriptome-driven functional basis with relevance to mental illness. Design, Setting, and Participants:This study used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, and connectivity analyses. A total of 20 688 participants in the UK Biobank, which includes clinical, genomic, and neuroimaging data, and 6 postmortem brains from neurotypical individuals in the Allen Human Brain Atlas (AHBA), including RNA microarray data. Data were extracted in February 2021 and analyzed between March and October 2021. Exposures:Genetic variants regulating levels and activity of circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were used as exposures in MR analyses. Main Outcomes and Measures:Brain imaging measures, including gray matter volume (GMV) and cortical thickness (CT), were used as outcomes. Associations were considered significant at a multiple testing-corrected threshold of P < 1.1 × 10-4. Differential gene expression in AHBA data was modeled in brain regions mapped to areas significant in MR analyses; genes were tested for biological and disease overrepresentation in annotation databases and for connectivity in protein-protein interaction networks. Results:Of 20 688 participants in the UK Biobank sample, 10 828 (52.3%) were female, and the mean (SD) age was 55.5 (7.5) years. In the UK Biobank sample, genetically predicted levels of IL-6 were associated with GMV in the middle temporal cortex (z score, 5.76; P = 8.39 × 10-9), inferior temporal (z score, 3.38; P = 7.20 × 10-5), fusiform (z score, 4.70; P = 2.60 × 10-7), and frontal (z score, -3.59; P = 3.30 × 10-5) cortex together with CT in the superior frontal region (z score, -5.11; P = 3.22 × 10-7). No significant associations were found for IL-1, IL-2, CRP, or BDNF after correction for multiple comparison. In the AHBA sample, 5 of 6 participants (83%) were male, and the mean (SD) age was 42.5 (13.4) years. Brain-wide coexpression analysis showed a highly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG), which further formed a highly connected protein-protein interaction network with IL-6 (enrichment test of expected vs observed network given the prevalence and degree of interactions in the STRING database: 43 nodes/30 edges observed vs 8 edges expected; mean node degree, 1.4; genome-wide significance, P = 4.54 × 10-9). MTG differentially expressed genes that were functionally enriched for biological processes in schizophrenia, autism spectrum disorder, and epilepsy. Conclusions and Relevance:In this study, genetically determined IL-6 was associated with brain structure and potentially affects areas implicated in developmental neuropsychiatric disorders, including schizophrenia and autism. 10.1001/jamapsychiatry.2022.0407
    Editorial: Mendelian Randomization Analysis Identifies Body Mass Index and Fasting Insulin as Potential Causal Risk Factors for Pancreatic Cancer Risk. Tsilidis Konstantinos K,Dai James Y,Peters Ulrike Journal of the National Cancer Institute 10.1093/jnci/djx043
    Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses. Brumpton Ben,Sanderson Eleanor,Heilbron Karl,Hartwig Fernando Pires,Harrison Sean,Vie Gunnhild Åberge,Cho Yoonsu,Howe Laura D,Hughes Amanda,Boomsma Dorret I,Havdahl Alexandra,Hopper John,Neale Michael,Nivard Michel G,Pedersen Nancy L,Reynolds Chandra A,Tucker-Drob Elliot M,Grotzinger Andrew,Howe Laurence,Morris Tim,Li Shuai, , ,Auton Adam,Windmeijer Frank,Chen Wei-Min,Bjørngaard Johan Håkon,Hveem Kristian,Willer Cristen,Evans David M,Kaprio Jaakko,Davey Smith George,Åsvold Bjørn Olav,Hemani Gibran,Davies Neil M Nature communications Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies. 10.1038/s41467-020-17117-4
    Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. Journal of the National Cancer Institute BACKGROUND:Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer. METHODS:We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants. RESULTS:Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)). CONCLUSION:This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk. 10.1093/jnci/djv178
    Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization. Zhang Ben,Shu Xiao-Ou,Delahanty Ryan J,Zeng Chenjie,Michailidou Kyriaki,Bolla Manjeet K,Wang Qin,Dennis Joe,Wen Wanqing,Long Jirong,Li Chun,Dunning Alison M,Chang-Claude Jenny,Shah Mitul,Perkins Barbara J,Czene Kamila,Darabi Hatef,Eriksson Mikael,Bojesen Stig E,Nordestgaard Børge G,Nielsen Sune F,Flyger Henrik,Lambrechts Diether,Neven Patrick,Wildiers Hans,Floris Giuseppe,Schmidt Marjanka K,Rookus Matti A,van den Hurk Katja,de Kort Wim L A M,Couch Fergus J,Olson Janet E,Hallberg Emily,Vachon Celine,Rudolph Anja,Seibold Petra,Flesch-Janys Dieter,Peto Julian,Dos-Santos-Silva Isabel,Fletcher Olivia,Johnson Nichola,Nevanlinna Heli,Muranen Taru A,Aittomäki Kristiina,Blomqvist Carl,Li Jingmei,Humphreys Keith,Brand Judith,Guénel Pascal,Truong Thérèse,Cordina-Duverger Emilie,Menegaux Florence,Burwinkel Barbara,Marme Frederik,Yang Rongxi,Surowy Harald,Benitez Javier,Zamora M Pilar,Perez Jose I A,Cox Angela,Cross Simon S,Reed Malcolm W R,Andrulis Irene L,Knight Julia A,Glendon Gord,Tchatchou Sandrine,Sawyer Elinor J,Tomlinson Ian,Kerin Michael J,Miller Nicola,Chenevix-Trench Georgia, ,Haiman Christopher A,Henderson Brian E,Schumacher Fredrick,Marchand Loic Le,Lindblom Annika,Margolin Sara,Hooning Maartje J,Martens John W M,Tilanus-Linthorst Madeleine M A,Collée J Margriet,Hopper John L,Southey Melissa C,Tsimiklis Helen,Apicella Carmel,Slager Susan,Toland Amanda E,Ambrosone Christine B,Yannoukakos Drakoulis,Giles Graham G,Milne Roger L,McLean Catriona,Fasching Peter A,Haeberle Lothar,Ekici Arif B,Beckmann Matthias W,Brenner Hermann,Dieffenbach Aida Karina,Arndt Volker,Stegmaier Christa,Swerdlow Anthony J,Ashworth Alan,Orr Nick,Jones Michael,Figueroa Jonine,Garcia-Closas Montserrat,Brinton Louise,Lissowska Jolanta,Dumont Martine,Winqvist Robert,Pylkäs Katri,Jukkola-Vuorinen Arja,Grip Mervi,Brauch Hiltrud,Brüning Thomas,Ko Yon-Dschun,Peterlongo Paolo,Manoukian Siranoush,Bonanni Bernardo,Radice Paolo,Bogdanova Natalia,Antonenkova Natalia,Dörk Thilo,Mannermaa Arto,Kataja Vesa,Kosma Veli-Matti,Hartikainen Jaana M,Devilee Peter,Seynaeve Caroline,Van Asperen Christi J,Jakubowska Anna,Lubiński Jan,Jaworska-Bieniek Katarzyna,Durda Katarzyna,Hamann Ute,Torres Diana,Schmutzler Rita K,Neuhausen Susan L,Anton-Culver Hoda,Kristensen Vessela N,Grenaker Alnæs Grethe I, ,Pierce Brandon L,Kraft Peter,Peters Ulrike,Lindstrom Sara,Seminara Daniela,Burgess Stephen,Ahsan Habibul,Whittemore Alice S,John Esther M,Gammon Marilie D,Malone Kathleen E,Tessier Daniel C,Vincent Daniel,Bacot Francois,Luccarini Craig,Baynes Caroline,Ahmed Shahana,Maranian Mel,Healey Catherine S,González-Neira Anna,Pita Guillermo,Alonso M Rosario,Álvarez Nuria,Herrero Daniel,Pharoah Paul D P,Simard Jacques,Hall Per,Hunter David J,Easton Douglas F,Zheng Wei Journal of the National Cancer Institute BACKGROUND:Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. METHODS:We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. RESULTS:The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8). CONCLUSIONS:Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer. 10.1093/jnci/djv219
    The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study. Johnson Kelsey E,Siewert Katherine M,Klarin Derek,Damrauer Scott M, ,Chang Kyong-Mi,Tsao Philip S,Assimes Themistocles L,Maxwell Kara N,Voight Benjamin F PLoS medicine BACKGROUND:A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). METHODS AND FINDINGS:Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. CONCLUSIONS:We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk. 10.1371/journal.pmed.1003302
    Causality Inference of Obesity and Cancer Risk by Mendelian Randomization Analysis: Are We There Yet? Journal of the National Cancer Institute 10.1093/jnci/djab103
    Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis. Journal of the National Cancer Institute BACKGROUND:Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS:Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS:In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS:Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis. 10.1093/jnci/djac011
    Educational attainment impacts drinking behaviors and risk for alcohol dependence: results from a two-sample Mendelian randomization study with ~780,000 participants. Rosoff Daniel B,Clarke Toni-Kim,Adams Mark J,McIntosh Andrew M,Davey Smith George,Jung Jeesun,Lohoff Falk W Molecular psychiatry Observational studies suggest that lower educational attainment (EA) may be associated with risky alcohol use behaviors; however, these findings may be biased by confounding and reverse causality. We performed two-sample Mendelian randomization (MR) using summary statistics from recent genome-wide association studies (GWAS) with >780,000 participants to assess the causal effects of EA on alcohol use behaviors and alcohol dependence (AD). Fifty-three independent genome-wide significant SNPs previously associated with EA were tested for association with alcohol use behaviors. We show that while genetic instruments associated with increased EA are not associated with total amount of weekly drinks, they are associated with reduced frequency of binge drinking ≥6 drinks (ß = -0.198, 95% CI, -0.297 to -0.099, P = 9.14 × 10), reduced total drinks consumed per drinking day (ß = -0.207, 95% CI, -0.293 to -0.120, P = 2.87 × 10), as well as lower weekly distilled spirits intake (ß = -0.148, 95% CI, -0.188 to -0.107, P = 6.24 × 10). Conversely, genetic instruments for increased EA were associated with increased alcohol intake frequency (ß = 0.331, 95% CI, 0.267-0.396, P = 4.62 × 10), and increased weekly white wine (ß = 0.199, 95% CI, 0.159-0.238, P = 7.96 × 10) and red wine intake (ß = 0.204, 95% CI, 0.161-0.248, P = 6.67 × 10). Genetic instruments associated with increased EA reduced AD risk: an additional 3.61 years schooling reduced the risk by ~50% (OR = 0.508, 95% CI, 0.315-0.819, P = 5.52 × 10). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our findings suggest EA may have important effects on alcohol consumption patterns and may provide potential mechanisms explaining reported associations between EA and adverse health outcomes. 10.1038/s41380-019-0535-9
    Diet-Derived Circulating Antioxidants and Risk of Coronary Heart Disease: A Mendelian Randomization Study. Luo Jiao,le Cessie Saskia,van Heemst Diana,Noordam Raymond Journal of the American College of Cardiology BACKGROUND:Previously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation. OBJECTIVES:The purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR). METHODS:Single-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, β-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed. RESULTS:Among an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for β-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for γ-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels. CONCLUSIONS:Evidence from our study did not support a protective effect of genetic predisposition to high dietary-derived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD. 10.1016/j.jacc.2020.10.048
    Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals. Rasmussen Katrine L,Tybjærg-Hansen Anne,Nordestgaard Børge G,Frikke-Schmidt Ruth Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established. METHODS:Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively. RESULTS:In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10 and 9 × 10). APOE-weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27-1.57) for Alzheimer's disease and 1.33 (1.25-1.43) for all dementia (F-statistics = 3821). DISCUSSION:Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship. 10.1016/j.jalz.2017.05.006
    The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study. Perry Benjamin I,Burgess Stephen,Jones Hannah J,Zammit Stan,Upthegrove Rachel,Mason Amy M,Day Felix R,Langenberg Claudia,Wareham Nicholas J,Jones Peter B,Khandaker Golam M PLoS medicine BACKGROUND:Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. METHODS AND FINDINGS:We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38-6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36-0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37-2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85-1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. CONCLUSIONS:Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance. 10.1371/journal.pmed.1003455
    Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Nazarzadeh Milad,Pinho-Gomes Ana-Catarina,Bidel Zeinab,Dehghan Abbas,Canoy Dexter,Hassaine Abdelaali,Ayala Solares Jose Roberto,Salimi-Khorshidi Gholamreza,Smith George Davey,Otto Catherine M,Rahimi Kazem European heart journal AIMS:Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. METHODS AND RESULTS:Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22-1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80-1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92-2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. CONCLUSION:Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention. 10.1093/eurheartj/ehaa070
    Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways. Jamieson Emily,Korologou-Linden Roxanna,Wootton Robyn E,Guyatt Anna L,Battram Thomas,Burrows Kimberley,Gaunt Tom R,Tobin Martin D,Munafò Marcus,Davey Smith George,Tilling Kate,Relton Caroline,Richardson Tom G,Richmond Rebecca C American journal of human genetics Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. We found evidence of a possible causal effect for DNA methylation on FEV at 18 CpGs (p < 1.2 × 10). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV, although DNA methylation at some sites might influence lung function via effects on smoking. By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results. 10.1016/j.ajhg.2020.01.015
    Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study. Lyall Donald M,Celis-Morales Carlos,Ward Joey,Iliodromiti Stamatina,Anderson Jana J,Gill Jason M R,Smith Daniel J,Ntuk Uduakobong Efanga,Mackay Daniel F,Holmes Michael V,Sattar Naveed,Pell Jill P JAMA cardiology Importance:Higher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear. Objectives:To use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization. Design, Setting, and Participants:Cross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data. Participants attended 1 of 22 assessment centers across the United Kingdom between 2006 and 2010. The present study was conducted from May 1 to July 11, 2016. Main Outcomes and Measures:Prevalence of hypertension, coronary heart disease, and type 2 diabetes were determined at assessment, based on self-report. Blood pressure was measured clinically. Participants self-reported sociodemographic information pertaining to relevant confounders. A polygenic risk score comprising 93 single-nucleotide polymorphisms associated with BMI from previous genome-wide association studies was constructed, and the genetic risk score was applied to derive causal estimates using a mendelian randomization approach. Results:Of the 119 859 individuals included in the study, 56 816 (47.4%) were men; mean (SD) age was 56.87 (7.93) years. Mendelian randomization analysis showed significant positive associations between genetically instrumented higher BMI and risk of hypertension (odds ratio [OR] per 1-SD higher BMI, 1.64; 95% CI, 1.48-1.83; P = 1.1 × 10-19), coronary heart disease (OR, 1.35; 95% CI, 1.09-1.69; P = .007) and type 2 diabetes (OR, 2.53; 95% CI, 2.04-3.13; P = 1.5 × 10-17), as well as systolic blood pressure (β = 1.65 mm Hg; 95% CI, 0.78-2.52 mm Hg; P = 2.0 × 10-04) and diastolic blood pressure (β  = 1.37 mm Hg; 95% CI, 0.88-1.85 mm Hg; P = 3.6 × 10-08). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history. Conclusions and Relevance:The results of this study add to the burgeoning evidence of an association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in many countries with increasing obesity levels. 10.1001/jamacardio.2016.5804
    Educational attainment and drinking behaviors: Mendelian randomization study in UK Biobank. Zhou Tao,Sun Dianjianyi,Li Xiang,Ma Hao,Heianza Yoriko,Qi Lu Molecular psychiatry Educational attainment has been associated with drinking behaviors in observation studies. We performed Mendelian randomization analysis to determine whether educational attainment causally affected drinking behaviors, including amount of alcohol intakes (in total and various types), drinking frequency, and drinking with or without meals among 334,507 white British participants from the UK Biobank cohort. We found that genetically instrumented higher education (1 additional year) was significantly related to higher total amount of alcohol intake (inverse-variance weighted method (IVW): beta = 0.44, 95% confidence interval (CI) 0.40-0.49, P = 1.57E-93). The causal relations with total amount and frequency of alcohol drinking were more evident among women. In analyses of different types of alcohol, higher educational attainment showed the strongest causal relation with more consumption of red wine (IVW beta = 0.34, 95% CI 0.32-0.36, P = 2.65E-247), followed by white wine/champagne, in a gender-specific manner. An inverse association was found for beer/cider and spirits. In addition, we found that 1 additional year of educational attainment was causally related to higher drinking frequency (IVW beta = 0.54, 95% CI 0.51-0.57, P = 4.87E-230) and a higher likelihood to take alcohol with meals (IVW: odds ratio (OR) = 3.10, 95% CI 2.93-3.29, P = 0.00E + 00). The results indicate causal relations of higher education with intake of more total alcohol especially red wine, and less beer/cider and spirits, more frequent drinking, and drinking with meals, suggesting the importance of improving drinking behaviors, especially among people with higher education. 10.1038/s41380-019-0596-9
    Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease Outcomes: A Mendelian Randomization Analysis. Lamina Claudia,Kronenberg Florian, JAMA cardiology Importance:Genetic and epidemiologic data suggest that lipoprotein(a) (Lp[a]) is one of the strongest genetically determined risk factors for coronary heart disease (CHD). Specific therapies to lower Lp(a) are on the horizon, but the required reduction of Lp(a) to translate into clinically relevant lowering of CHD outcomes is a matter of debate. Objective:To estimate the required Lp(a)-lowering effect size that may be associated with a reduction of CHD outcomes compared with the effect size of low-density lipoprotein cholesterol (LDL-C)-lowering therapies. Design, Setting, and Participants:Genetic epidemiologic study using a mendelian randomization analysis to estimate the required Lp(a)-lowering effect size for a clinically meaningful effect on outcomes. We used the effect estimates for Lp(a) from a genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry. All Lp(a) measurements were performed in 1 laboratory. Genetic estimates for 27 single-nucleotide polymorphisms on Lp(a) concentrations were used. Odds ratios for these 27 single-nucleotide polymorphisms associated with CHD risk were retrieved from a subsample of the CHD Exome+ consortium. Exposures:Genetic LPA score, plasma Lp(a) concentrations, and observations of statin therapies on CHD outcomes. Main Outcomes and Measures:Coronary heart disease. Results:The study included 13 781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. Four of the studies were similar in age distribution (means between 51 and 59 years), and 1 cohort was younger; mean age, 32 years. The frequency of women was similar between 51% and 55%. We estimated that the required reduction in Lp(a) effect size would be 65.7 mg/dL (95% CI, 46.3-88.3) to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL (to convert to millimoles per liter, multiply by 0.0259). Conclusions and Relevance:This mendelian randomization analysis estimated a required Lp(a)-lowering effect size of 65.7 mg/dL to reach the same effect as a 38.67-mg/dL lowering of LDL-C. However, this estimate is determined by the observed effect estimates of single-nucleotide polymorphisms on Lp(a) concentrations and is therefore influenced by the standardization of the Lp(a) assay used. As a consequence, calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past. 10.1001/jamacardio.2019.1041
    Nongenetic Factors Associated With Psychotic Experiences Among UK Biobank Participants: Exposome-Wide Analysis and Mendelian Randomization Analysis. JAMA psychiatry Importance:Although hypothesis-driven research has identified several factors associated with psychosis, this one-exposure-to-one-outcome approach fails to embrace the multiplicity of exposures. Systematic approaches, similar to agnostic genome-wide analyses, are needed to identify genuine signals. Objective:To systematically investigate nongenetic correlates of psychotic experiences through data-driven agnostic analyses and genetically informed approaches to evaluate associations. Design, Setting, Participants:This cohort study analyzed data from the UK Biobank Mental Health Survey from January 1 to June 1, 2021. An exposome-wide association study was performed in 2 equal-sized split discovery and replication data sets. Variables associated with psychotic experiences in the exposome-wide analysis were tested in a multivariable model. For the variables associated with psychotic experiences in the final multivariable model, the single-nucleotide variant-based heritability and genetic overlap with psychotic experiences using linkage disequilibrium score regression were estimated, and mendelian randomization (MR) approaches were applied to test potential causality. The significant associations observed in 1-sample MR analyses were further tested in multiple sensitivity tests, including collider-correction MR, 2-sample MR, and multivariable MR analyses. Exposures:After quality control based on a priori criteria, 247 environmental, lifestyle, behavioral, and economic variables. Main Outcomes and Measures:Psychotic experiences. Results:The study included 155 247 participants (87 896 [57%] female; mean [SD] age, 55.94 [7.74] years). In the discovery data set, 162 variables (66%) were associated with psychotic experiences. Of these, 148 (91%) were replicated. The multivariable analysis identified 36 variables that were associated with psychotic experiences. Of these, 28 had significant genetic overlap with psychotic experiences. One-sample MR analyses revealed forward associations with 3 variables and reverse associations with 3. Forward associations with ever having experienced sexual assault and pleiotropy of risk-taking behavior and reverse associations without pleiotropy of experiencing a physically violent crime as well as cannabis use and the reverse association with pleiotropy of worrying too long after embarrassment were confirmed in sensitivity tests. Thus, associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables. For several variables, the direction of the association was reversed in the final multivariable and MR analyses. Conclusions and Relevance:The findings of this study underscore the need for systematic approaches and triangulation of evidence to build a knowledge base from ever-growing observational data to guide population-level prevention strategies for psychosis. 10.1001/jamapsychiatry.2022.1655
    High Blood Pressure and Risk of Dementia: A Two-Sample Mendelian Randomization Study in the UK Biobank. Sproviero William,Winchester Laura,Newby Danielle,Fernandes Marco,Shi Liu,Goodday Sarah M,Prats-Uribe Albert,Alhambra Daniel P,Buckley Noel J,Nevado-Holgado Alejo J Biological psychiatry BACKGROUND:Findings from randomized controlled trials have yielded conflicting results on the association between blood pressure (BP) and dementia traits. We tested the hypothesis that a causal relationship exists between systolic BP (SBP) and/or diastolic BP (DBP) and risk of Alzheimer's disease (AD). METHODS:We performed a generalized summary Mendelian randomization (GSMR) analysis using summary statistics of a genome-wide association study meta-analysis of 299,024 individuals of SBP or DBP as exposure variables against three different outcomes: 1) AD diagnosis (International Genomics of Alzheimer's Project), 2) maternal family history of AD (UK Biobank), and 3) paternal family history of AD (UK Biobank). Finally, a combined meta-analysis of 368,440 individuals that included these three summary statistics was used as final outcome. RESULTS:GSMR applied to the International Genomics of Alzheimer's Project dataset revealed a significant effect of high SBP lowering the risk of AD (β = -0.19, p = .04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [β = -0.12, p = .02], DBP [β = -0.10, p = .05]) and to the paternal family history of AD UK Biobank dataset (SBP [β = -0.16, p = .02], DBP [β = -0.24, p = 7.4 × 10]) showed the same effect. A subsequent combined meta-analysis confirmed the overall significant effect for the other SBP analyses (β = -0.14, p = .03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (β = -0.14, p = .03). CONCLUSIONS:A causal effect exists between high BP and a reduced late-life risk of AD. The results were obtained through careful consideration of confounding factors and the application of complementary MR methods on independent cohorts. 10.1016/j.biopsych.2020.12.015
    Associations between moderate alcohol consumption, brain iron, and cognition in UK Biobank participants: Observational and mendelian randomization analyses. PLoS medicine BACKGROUND:Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits. METHODS AND FINDINGS:Observational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR). Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the "Snap" card game. Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never drinkers comprised 2.7% of the sample. Alcohol consumption was associated with markers of higher iron (χ) in putamen (β = 0.08 standard deviation (SD) [95% confidence interval (CI) 0.06 to 0.09], p < 0.001), caudate (β = 0.05 [0.04 to 0.07], p < 0.001), and substantia nigra (β = 0.03 [0.02 to 0.05], p < 0.001) and lower iron in the thalami (β = -0.06 [-0.07 to -0.04], p < 0.001). Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly. MR analyses provided weak evidence these relationships are causal. Genetically predicted alcoholic drinks weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections. Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction. Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f. <7 units (56 g). Systemic iron levels partially mediated associations of alcohol intake with brain iron. Markers of higher basal ganglia iron associated with slower executive function, lower fluid intelligence, and slower reaction times. The main limitations of the study include that χ and T2* can reflect changes in myelin as well as iron, alcohol use was self-reported, and MR estimates can be influenced by genetic pleiotropy. CONCLUSIONS:To the best of our knowledge, this study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline. 10.1371/journal.pmed.1004039
    An Exposure-Wide and Mendelian Randomization Approach to Identifying Modifiable Factors for the Prevention of Depression. The American journal of psychiatry OBJECTIVE:Efforts to prevent depression, the leading cause of disability worldwide, have focused on a limited number of candidate factors. Using phenotypic and genomic data from over 100,000 UK Biobank participants, the authors sought to systematically screen and validate a wide range of potential modifiable factors for depression. METHODS:Baseline data were extracted for 106 modifiable factors, including lifestyle (e.g., exercise, sleep, media, diet), social (e.g., support, engagement), and environmental (e.g., green space, pollution) variables. Incident depression was defined as minimal depressive symptoms at baseline and clinically significant depression at follow-up. At-risk individuals for incident depression were identified by polygenic risk scores or by reported traumatic life events. An exposure-wide association scan was conducted to identify factors associated with incident depression in the full sample and among at-risk individuals. Two-sample Mendelian randomization was then used to validate potentially causal relationships between identified factors and depression. RESULTS:Numerous factors across social, sleep, media, dietary, and exercise-related domains were prospectively associated with depression, even among at-risk individuals. However, only a subset of factors was supported by Mendelian randomization evidence, including confiding in others (odds ratio=0.76, 95% CI=0.67, 0.86), television watching time (odds ratio=1.09, 95% CI=1.05, 1.13), and daytime napping (odds ratio=1.34, 95% CI=1.17, 1.53). CONCLUSIONS:Using a two-stage approach, this study validates several actionable targets for preventing depression. It also demonstrates that not all factors associated with depression in observational research may translate into robust targets for prevention. A large-scale exposure-wide approach combined with genetically informed methods for causal inference may help prioritize strategies for multimodal prevention in psychiatry. 10.1176/appi.ajp.2020.19111158
    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
    Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. European heart journal AIMS:Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk. METHODS AND RESULTS:The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants.We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8- 7.3%). CONCLUSION:Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status. 10.1093/eurheartj/ehab809
    Association between alcohol consumption and Alzheimer's disease: A Mendelian randomization study. Andrews Shea J,Goate Alison,Anstey Kaarin J Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Observational studies have suggested that light-to-moderate alcohol consumption decreases the risk of Alzheimer's disease, but it is unclear if this association is causal. METHODS:Two-sample Mendelian randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence, or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late-Onset Alzheimer's disease (LOAD) or Alzheimer's disease age of onset survival (AAOS). Additionally, γ-glutamyltransferase levels were included as a positive control. RESULTS:There was no evidence of a causal association between alcohol consumption, alcohol dependence, or AUDIT, and LOAD. Alcohol consumption was associated with an earlier AAOS and increased γ-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS. DISCUSSION:MR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias. 10.1016/j.jalz.2019.09.086
    Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study. Kappelmann Nils,Arloth Janine,Georgakis Marios K,Czamara Darina,Rost Nicolas,Ligthart Symen,Khandaker Golam M,Binder Elisabeth B JAMA psychiatry Importance:Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. Objective:To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS Data Sources:Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204 402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117 907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386 533 individuals); body mass index (BMI) (up to 322 154 individuals); and height (up to 253 280 individuals). Design:In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. Results:Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. Conclusions and Relevance:This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strategy for suicide prevention. 10.1001/jamapsychiatry.2020.3436
    A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease. Brain : a journal of neurology There is increasing evidence on inflammation as a determinant in the pathogenesis of Parkinson's disease. But, its role in parkinsonian neurodegeneration remains elusive: it´s not clear if inflammatory cascades are causes or consequences of dopamine neurons death. In the present study, we aim at performing an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest to date genome-wide association studies (sample size ranging from 13,955 to 204,402 individuals) conducted on European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist, and tumor necrosis factor α. Genetic association data on Parkinson's disease (56,306 cases and 1,417,791 controls) and age at onset of Parkinson's disease (28,568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2<0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check findings' consistency. In all the three data sources selected for interleukin-6, we found statistical evidence for earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration (years difference per 1 log-unit increase = -2.364, 95% CI = -4.789 to 0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247; ). We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist, and tumor necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease. 10.1093/brain/awac193
    Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: A multivariable Mendelian randomization study. Rosoff Daniel B,Davey Smith George,Mehta Nehal,Clarke Toni-Kim,Lohoff Falk W PLoS medicine BACKGROUND:Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events. METHODS AND FINDINGS:Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04-0.47, P value = 1.72 × 10-28), triglycerides (TRG) (beta -0.23, 95% CI, -0.30, -0.15, P value = 4.69 × 10-10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03-0.18, P value = 4.72 × 10-3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03-0.16, P value = 5.24 × 10-3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014-0.027, P value = 6.59 × 10-12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03-1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01-1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01-1.03, P value = 5.56 × 10-4). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37, P value = 2.0 × 10-6), CHD (OR = 1.64, 95% CI, 1.28-2.09, P value = 8.07 × 10-5), heart failure (HF) (OR = 1.61, 95% CI, 1.32-1.95, P value = 1.9 × 10-6), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41-4.07, P value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10-2.84, P value = 0.02), HF (OR = 1.67, 95% CI, 1.14-2.46, P value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38-4.01, P value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations. CONCLUSIONS:Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk. 10.1371/journal.pmed.1003410
    Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank. Malik Rainer,Georgakis Marios K,Neitzel Julia,Rannikmäe Kristiina,Ewers Michael,Seshadri Sudha,Sudlow Cathie L M,Dichgans Martin Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. METHODS:Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. RESULTS:Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). DISCUSSION:These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk. 10.1002/alz.12320
    Mendelian randomization analyses for PCOS: evidence, opportunities, and challenges. Trends in genetics : TIG Identifying etiological risk factors is significant for preventing and treating patients with polycystic ovary syndrome (PCOS). Through genetic variation, Mendelian randomization (MR) assesses causal associations between PCOS risk and related exposure factors. This emerging technology has provided evidence of causal associations of anti-Müllerian hormone (AMH) levels, sex hormone-binding globulin (SHBG) levels, menopause age, adiposity, insulin resistance (IR), depression, breast cancer, ovarian cancer, obsessive-compulsive disorder (OCD), and forced vital capacity (FVC) with PCOS, while lacking associations of type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), stroke, anxiety disorder (AD), schizophrenia (SCZ), bipolar disorder (BIP), and offspring birth weight with PCOS. In this review, we briefly introduce the concept and methodology of MR in terms of the opportunities and challenges in this field based on recent results obtained from MR analyses involving PCOS. 10.1016/j.tig.2022.01.005
    Elevated body mass index as a causal risk factor for symptomatic gallstone disease: a Mendelian randomization study. Stender Stefan,Nordestgaard Børge G,Tybjaerg-Hansen Anne Hepatology (Baltimore, Md.) UNLABELLED:Elevated body mass index (BMI) is associated with an increased risk of gallstone disease. Whether this reflects a causal association is unknown. Using a Mendelian randomization approach, we studied 77,679 individuals from the general population. Of these, 4,106 developed symptomatic gallstone disease during up to 34 years of follow-up. Subjects were genotyped for three common variants known to associate with BMI: FTO(rs9939609); MC4R(rs17782313); and TMEM18(rs6548238). The number of BMI-increasing alleles was calculated for each participant. In observational analyses, mean baseline BMI was 55% (11.6 kg/m(2) ) increased in individuals in the fifth quintile versus the first quintile, similar in women and men. The corresponding multifactorially adjusted hazard ratio (HR) for symptomatic gallstone disease was 2.84 (95% confidence interval [CI]: 2.32-3.46) overall, 3.36 (95% CI: 2.62-4.31) in women, and 1.51 (95% CI: 1.09-2.11) in men (P trend: 0.001 to <0.001; P interaction: BMI*sex on risk = 0.01). In genetic analyses, carrying 6 versus 0-1 BMI-increasing alleles was associated with a 5.2% (1.3 kg/m(2) ) increase in BMI overall and with increases of 4.3% in women and 6.1% in men (all P trend: <0.001). Corresponding HRs for symptomatic gallstone disease were 1.43 (95% CI: 0.99-2.05) overall, 1.54 (95% CI: 1.00-2.35) in women, and 1.19 (95% CI: 0.60-2.38) in men (P trend = 0.007, 0.02, and 0.26, respectively; P interaction allele score*sex on risk = 0.49). The estimated causal odds ratio (OR) for symptomatic gallstone disease, by instrumental variable analysis for a 1 kg/m(2) increase in genetically determined BMI, was 1.17 (95% CI: 0.99-1.37) overall and 1.20 (95% CI: 1.00-1.44) and 1.02 (95% CI: 0.90-1.16) in women and men, respectively. Corresponding observational HRs were 1.07 (95% CI: 1.06-1.08), 1.08 (95% CI: 1.07-1.10), and 1.04 (95% CI: 1.02-1.07), respectively. CONCLUSION:These results are compatible with a causal association between elevated BMI and increased risk of symptomatic gallstone disease, which is most pronounced in women. 10.1002/hep.26563
    Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. PLoS medicine BACKGROUND:Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS:We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS:In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications. 10.1371/journal.pmed.1003897
    Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization. Circulation BACKGROUND:Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. METHODS:We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using -protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis. RESULTS:Forty-four of ninety proteins were positively associated with risk of incident HF (<6.0×10). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. CONCLUSIONS:We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases. 10.1161/CIRCULATIONAHA.121.056663
    Mendelian randomization analysis of 37 clinical factors and coronary artery disease in East Asian and European populations. Genome medicine BACKGROUND:Coronary artery disease (CAD) remains the leading cause of mortality worldwide despite enormous efforts devoted to its prevention and treatment. While many genetic loci have been identified to associate with CAD, the intermediate causal risk factors and etiology have not been fully understood. This study assesses the causal effects of 37 heritable clinical factors on CAD in East Asian and European populations. METHODS:We collected genome-wide association summary statistics of 37 clinical factors from the Biobank Japan (42,793 to 191,764 participants) and the UK Biobank (314,658 to 442,817 participants), paired with summary statistics of CAD from East Asians (29,319 cases and 183,134 controls) and Europeans (91,753 cases and 311,344 controls). These clinical factors covered 12 cardiometabolic traits, 13 hematological indices, 7 hepatological and 3 renal function indices, and 2 serum electrolyte indices. We performed univariable and multivariable Mendelian randomization (MR) analyses in East Asians and Europeans separately, followed by meta-analysis. RESULTS:Univariable MR analyses identified reliable causal evidence (P < 0.05/37) of 10 cardiometabolic traits (height, body mass index [BMI], blood pressure, glycemic and lipid traits) and 4 other clinical factors related to red blood cells (red blood cell count [RBC], hemoglobin, hematocrit) and uric acid (UA). Interestingly, while generally consistent, we identified population heterogeneity in the causal effects of BMI and UA, with higher effect sizes in East Asians than those in Europeans. After adjusting for cardiometabolic factors in multivariable MR analysis, red blood cell traits (RBC, meta-analysis odds ratio 1.07 per standard deviation increase, 95% confidence interval 1.02-1.13; hemoglobin, 1.10, 1.03-1.16; hematocrit, 1.10, 1.04-1.17) remained significant (P < 0.05), while UA showed an independent causal effect in East Asians only (1.12, 1.06-1.19, P = 3.26×10). CONCLUSIONS:We confirmed the causal effects of 10 cardiometabolic traits on CAD and identified causal risk effects of RBC, hemoglobin, hematocrit, and UA independent of traditional cardiometabolic factors. We found no causal effects for 23 clinical factors, despite their reported epidemiological associations. Our findings suggest the physiology of red blood cells and the level of UA as potential intervention targets for the prevention of CAD. 10.1186/s13073-022-01067-1
    Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches. American journal of human genetics Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. When considering genetic variants in a single genetic region, both approaches can be performed. While a positive colocalization finding typically implies a non-zero Mendelian randomization estimate, the reverse is not generally true: there are several scenarios which would lead to a non-zero Mendelian randomization estimate but lack evidence for colocalization. These include the existence of distinct but correlated causal variants for the exposure and outcome, which would violate the Mendelian randomization assumptions, and a lack of strong associations with the outcome. As colocalization was developed in the GWAS tradition, typically evidence for colocalization is concluded only when there is strong evidence for associations with both traits. In contrast, a non-zero estimate from Mendelian randomization can be obtained despite only nominally significant genetic associations with the outcome at the locus. In this review, we discuss how the two approaches can provide complementary information on potential therapeutic targets. 10.1016/j.ajhg.2022.04.001
    When Will Mendelian Randomization Become Relevant for Clinical Practice and Public Health? Davey Smith George,Paternoster Lavinia,Relton Caroline JAMA 10.1001/jama.2016.21189
    Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization. Chatterjee Neal A,Giulianini Franco,Geelhoed Bastiaan,Lunetta Kathryn L,Misialek Jeffrey R,Niemeijer Maartje N,Rienstra Michiel,Rose Lynda M,Smith Albert V,Arking Dan E,Ellinor Patrick T,Heeringa Jan,Lin Honghuang,Lubitz Steven A,Soliman Elsayed Z,Verweij Niek,Alonso Alvaro,Benjamin Emelia J,Gudnason Vilmundur,Stricker Bruno H C,Van Der Harst Pim,Chasman Daniel I,Albert Christine M Circulation BACKGROUND:Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS:We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS:In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (: 0.43 [95% confidence interval, 0.32-0.54] kg/m per A-allele, <0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m per 1-U increase, <0.001) and incident AF (, hazard ratio, 1.07 [1.02-1.11] per A-allele, =0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, <0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m, =0.005 () and 1.11 (1.05-1.17) per kg/m, <0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m, <0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS:Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF. 10.1161/CIRCULATIONAHA.116.024921
    Mendelian randomization in (epi)genetic epidemiology: an effective tool to be handled with care. Latvala Antti,Ollikainen Miina Genome biology A study examining blood lipid traits takes epigenomics approaches to the next level by using carefully performed Mendelian randomization to assess causality rather than simply reporting associations.See related research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1000-6. 10.1186/s13059-016-1018-9
    Difficulties in Testing the Instrument Strength Independent of Direct Effect Assumption in Mendelian Randomization. Bowden Jack,Burgess Stephen,Smith George Davey JAMA cardiology 10.1001/jamacardio.2017.1572
    Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. Ference Brian A,Majeed Faisal,Penumetcha Raju,Flack John M,Brook Robert D Journal of the American College of Cardiology BACKGROUND:Considerable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD). OBJECTIVES:This study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD. METHODS:We constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design. RESULTS:A total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932). CONCLUSIONS:The effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C. 10.1016/j.jacc.2015.02.020
    Interleukin-6 Receptor and Inflammatory Bowel Disease: A Mendelian Randomization Study. Liu Guiyou,Jin Shuilin,Jiang Qinghua Gastroenterology 10.1053/j.gastro.2018.09.059