A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese.
Cancer science
Causal inference is one of the challenges in epidemiologic studies. Gynecologic diseases have been reported to have association with obesity, however the causality remained controversial except for uterine endometrial cancer. We conducted two-sample Mendelian randomization (MR) analysis using the large-scale genome-wide association study (GWAS) results of gynecologic diseases and body mass index (BMI) in the Japanese population to assess causal effect of BMI on gynecologic diseases. We first conducted GWAS of ovarian cancer, uterine endometrial cancer, uterine cervical cancer, endometriosis, and uterine fibroid (n = 647, 909, 538, 5236, and 645 cases, respectively, and 39 556 shared female controls), and BMI (81 610 males and non-overlapping 23 924 females). We then applied two-sample MR using 74 BMI-associated variants as instrumental variables. We observed significant causal effect of increased BMI on uterine endometrial cancer (β = 0.735, P = .0010 in inverse variance-weighted analysis), which is concordant with results of European studies. Causal effect of obesity was not apparent in the other gynecologic diseases tested. Our MR analyses provided strong evidence of the causal role of obesity in gynecologic diseases etiology, and suggested a possible preventive effect of intervention for obesity.
10.1111/cas.14667
Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers.
International journal of molecular sciences
Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.
10.3390/ijms22116083
Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus.
Kho Pik Fang,Mortlock Sally, , ,Rogers Peter A W,Nyholt Dale R,Montgomery Grant W,Spurdle Amanda B,Glubb Dylan M,O'Mara Tracy A
Human genetics
Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.
10.1007/s00439-021-02312-0
Polygenic risk score phenome-wide association study reveals an association between endometriosis and testosterone.
BMC medicine
BACKGROUND:Endometriosis affects 1 in 9 women, yet it is poorly understood with long diagnostic delays, invasive diagnoses, and poor treatment outcomes. Characterised by the presence of endometrial-like tissue outside of the uterus, its main symptoms are pain and infertility. Endometriosis often co-occurs with other conditions, which may provide insights into the origins of endometriosis. METHODS:Here a polygenic risk score phenome-wide association study of endometriosis was conducted in the UK Biobank to investigate the pleiotropic effects of a genetic liability to endometriosis. The relationship between the polygenic risk score for endometriosis and health conditions, blood and urine biomarkers and reproductive factors were investigated separately in females, males and females without an endometriosis diagnosis. The relationship between endometriosis and the blood and urine biomarkers was further investigated using genetic correlation and Mendelian randomisation approaches to identify causal relationships. RESULTS:Multiple health conditions, blood and urine biomarkers and reproductive factors were associated with genetic liability to endometriosis in each group, indicating many endometriosis comorbidities are not dependent on the physical manifestation of endometriosis. Differences in the associated traits between males and females highlighted the importance of sex-specific pathways in the overlap of endometriosis with many other traits. Notably, an association of genetic liability to endometriosis with lower testosterone levels was identified. Follow-up analysis utilising Mendelian randomisation approaches suggested lower testosterone may be causal for both endometriosis and clear cell ovarian cancer. CONCLUSIONS:This study highlights the diversity of the pleiotropic effects of genetic risk to endometriosis irrespective of a diagnosis of endometriosis. A key finding was the identification of a causal effect of the genetic liability to lower testosterone on endometriosis using Mendelian randomisation.
10.1186/s12916-023-03184-z
Genetically identification of endometriosis and cancers risk in women through a two-sample Mendelian randomization study.
Scientific reports
Endometriosis is a prevalent and chronic inflammatory gynecologic disorder affecting approximately 6-10% of women globally, and has been associated with an increased risk of cancer. Nevertheless, previous studies have been hindered by methodological limitations that compromise the validity and robustness of their findings. In this study we conducted a comprehensive two-sample Mendelian randomization analysis to explore the genetically driven causal relationship between endometriosis and the risk of cancer. We conducted the analysis via the inverse variance weighted method, MR Egger method, and weighted median method utilizing publicly available genome-wide association study summary statistics. Furthermore, we implemented additional sensitivity analyses to assess the robustness and validity of the causal associations identified. We found strong evidence of a significant causal effect of endometriosis on a higher risk of ovarian cancer via inverse-variance weighted method (OR = 1.19, 95% CI 1.11-1.29, p < 0.0001), MR-Egger regression, and weighted median methodologies. Remarkably, our findings revealed a significant association between endometriosis and an increased risk of clear cell ovarian cancer (OR = 2.04, 95% CI 1.66-2.51, p < 0.0001) and endometrioid ovarian cancer (OR = 1.45, 95% CI 1.27-1.65, p < 0.0001). No association between endometriosis and other types of cancer was observed. We uncovered a causal relationship between endometriosis and an elevated risk of ovarian cancer, particularly clear cell ovarian cancer and endometrioid ovarian cancer. No significant associations between endometriosis and other types of cancer could be identified.
10.1038/s41598-024-58950-7
Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study.
Frontiers in endocrinology
Background:Testosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies. Methods:We leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates. Results:The results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031). Conclusion:Our analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.
10.3389/fendo.2023.1161356
Epidemiologic and genetic associations of female reproductive disorders with depression or dysthymia: a Mendelian randomization study.
Scientific reports
Observational studies have previously reported an association between depression and certain female reproductive disorders. However, the causal relationships between depression and different types of female reproductive disorders remain unclear in terms of direction and magnitude. We conducted a comprehensive investigation using a two-sample bi-directional Mendelian randomization analysis, incorporating publicly available GWAS summary statistics. Our aim was to establish a causal relationship between genetically predicted depression and the risk of various female reproductive pathological conditions, such as ovarian dysfunction, polycystic ovary syndrome(PCOS), ovarian cysts, abnormal uterine and vaginal bleeding(AUB), endometriosis, leiomyoma of the uterus, female infertility, spontaneous abortion, eclampsia, pregnancy hypertension, gestational diabetes, excessive vomiting in pregnancy, cervical cancer, and uterine/endometrial cancer. We analyzed a substantial sample size, ranging from 111,831 to 210,870 individuals, and employed robust statistical methods, including inverse variance weighted, MR-Egger, weighted median, and MR-PRESSO, to estimate causal effects. Sensitivity analyses, such as Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots, were also conducted to ensure the validity of our results. Furthermore, risk factor analyses were performed to investigate potential mediators associated with these observed relationships. Our results demonstrated that genetic predisposition to depression or dysthymia was associated with an increased risk of developing PCOS (OR = 1.43, 95% CI 1.28-1.59; P = 6.66 × 10), ovarian cysts (OR = 1.36, 95% CI 1.20-1.55; P = 1.57 × 10), AUB (OR = 1.41, 95% CI 1.20-1.66; P = 3.01 × 10), and endometriosis (OR = 1.43, 95% CI 1.27-1.70; P = 2.21 × 10) after Bonferroni correction, but no evidence for reverse causality. Our study did not find any evidence supporting a causal or reverse causal relationship between depression/dysthymia and other types of female reproductive disorders. In summary, our study provides evidence for a causal relationship between genetically predicted depression and specific types of female reproductive disorders. Our findings emphasize the importance of depression management in the prevention and treatment of female reproductive disorders, notably including PCOS, ovarian cysts, AUB, and endometriosis.
10.1038/s41598-024-55993-8
Causal Relationship Between Mood Swing and Gynecological Disorders: A Mendelian Randomization Study.
International journal of women's health
Background:Gynecological disorders are a wide range of health problems affecting the female reproductive system, which poses substantial health challenges worldwide. Increasing number of observational studies have associated mood instability to common female diseases, but the underlying causal relationship remains unclear. In this work, Mendelian randomization (MR) analysis was applied to explore the genetically predicted causal relationship of mood swings and several prevalent gynecological disorders. Methods:Instrumental variables (IVs) of mood swings were selected from UK Biobank (UKB), with 204,412 cases and 247,207 controls being incorporated. The genetic variants for female disorders were obtained from genome-wide association studies (GWASs) and FinnGen consortium. To avoid biases caused by racial difference, only European population was included here. Five strong analytical methodologies were used to increase the validity of the results, the most substantial of which was the inverse variance weighting (IVW) method. Pleiotropy, sensitivity, and heterogeneity were assessed to strengthen the findings. Results:We found mood swings was significantly positively associated with risk of endometrial cancer (OR= 2.60 [95% CI= 1.36, 4.95], P= 0.0037), cervical cancer (OR= 1.01[95% CI= 1.00,1.02], P= 0.0213) and endometriosis (OR= 2.58 [95% CI= 1.18, 5.60], P= 0.0170) by IVW method. However, there was no causal relationship between mood swing and ovarian cancer. No pleiotropy and heterogeneity existed and sensitivity tests were passed. Conclusion:This study reveals that mood swing may serve as a genetically predicted causal risk factor for endometrial cancer, cervical cancer, and endometriosis in the European population, while no such association was observed for ovarian cancer. These findings make up for observational research's inherent limitations and may improve patient outcomes in the field of gynecological health. However, the study's focus on European populations may limit the applicability of these results globally.
10.2147/IJWH.S468624
Health outcomes of age at menarche in European women: a two-sample Mendelian randomization study.
Postgraduate medical journal
BACKGROUND:Observational studies have shown an association between age at menarche (AAM) and the risk of gynecological diseases. However, the causality cannot be determined due to residual confounding. METHODS:We conducted a Mendelian randomization (MR) study to evaluate the causal effect of AAM on several gynecological diseases, including endometriosis, female infertility, pre-eclampsia or eclampsia, uterine fibroids, breast cancer, ovarian cancer, and endometrial cancer. Single nucleotide polymorphisms were used as genetic instruments. The inverse variance weighted method was used as the primary approach and several other MR models were conducted for comparison. Cochran's Q test, Egger's intercept test, and leave-one-out analysis were conducted for sensitivity analysis. Radial MR analysis was conducted when detecting the existence of heterogeneity. RESULTS:After Bonferroni correction and thorough sensitivity analysis, we observed a robust causal effect of AAM on endometrial cancer (odds ratio: 0.80; 95% confidence interval: 0.72-0.89; P = 4.61 × 10-5) and breast cancer (odds ratio: 0.94; 95% confidence interval: 0.90-0.98; P = .003). Sensitivity analysis found little evidence of horizontal pleiotropy. The inverse variance weighted method also detected weak evidence of associations of AAM with endometriosis and pre-eclampsia or eclampsia. CONCLUSIONS:This MR study demonstrated a causal effect of AAM on gynecological diseases, especially for breast cancer and endometrial cancer, which indicates AAM might be a promising index to use for disease screening and prevention in clinical practice. Key messages What is already known on this topic - Observational studies have reported associations between age at menarche (AAM) and a variety of gynecological diseases but the causality has not been determined. What this study adds - This Mendelian randomization study demonstrated that AAM causally affects the risk of breast cancer and endometrial cancer. How this study might affect research, practice, or policy - The findings of our study imply that AAM could be a candidate marker for early screening of populations at higher risk of breast cancer and endometrial cancer.
10.1093/postmj/qgad023
A cause-effect relationship between uterine diseases and breast cancer: A bidirectional Mendelian randomization study.
Heliyon
Objective:To explore the cause-effect relationship between uterine diseases (UDs) and breast cancer (BC) and underlying mechanism of the cause-effect relationship, enhance understanding of the association between BC and UDs. Methods:A two-sample bidirectional Mendelian randomization (MR) analysis was conducted. We obtained summary statistics data from GWAS for BC, endometriosis, endometrial cancer (EC), uterine leiomyoma (UL), uterine polyps (UP), and cervical cancer (CC). Independent SNPs were selected as instrumental variables (IVs) for each disease. The inverse variance weighted (IVW) method was primary used for estimating the causal association between UDs and BC. To further evaluate the consistency and dependability of the results, we also utilized the weighted median, weighted mode, simple mode, and MR-Egger methods, along with sensitivity analyses. Furthermore, a supplementary analysis focusing on the variants linked to BC and UDs was conducted. This involved identifying corresponding genes and subsequently performing KEGG/GO analyses to investigate potential molecular mechanisms. Results:The results indicated significant associations between genetic susceptibility to endometriosis, EC, and UL with BC risk. The odds ratios (ORs) were as follows: endometriosis at 0.963 (95 % CI, 0.942-0.984; = 7.11e-5), EC at 1.056 (95 % CI, 1.033-1.081; = 2.39e-6), and UL at 1.027 (95 % CI, 1.006-1.048; = 0.010). Conversely, the predisposition to BC inferred from genetic factors was markedly correlated with an elevated risk of EC indicated by an OR of 1.066 (95 % CI, 1.019-1.116; = 0.006), and was correlated with UP risk (OR, 1.001,95 % CI, 1.000-1.002; = 0.001).Sensitivity analyses provided weak evidence for these effects, suggesting that the study's outcomes are consistent and trustworthy. Further analysis of the genetic variants associated with BC, and these related genes are enriched in Cellular senescence, GnRH secretion, Phosphatidylinositol signaling system, and so on. Conclusion:This study corroborates the existence of a reciprocal causal relationship between BC and EC, as well as highlighting the substantial correlations between a genetic susceptibility to UL and endometriosis with BC. BC may exert their influence on EC and UP through Cellular senescence, GnRH secretion, and other pathways. These discoveries offer fresh perspectives on the genetic pathogenesis of BC and UDs, and can guide future experimental studies. Additionally, they lay down a groundwork for the development of tailored preventative and therapeutic strategies moving forward.
10.1016/j.heliyon.2024.e38130