scholarly journals Mendelian randomization analysis identified potential genes pleiotropically associated with polycystic ovary syndrome

2021 ◽  
Author(s):  
Qian Sun ◽  
Yuan Gao ◽  
Jingyun Yang ◽  
Jiayi Lu ◽  
Wen Feng ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Whole Blood ◽  
Multiple Testing ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Research Question ◽  
Ovary Syndrome ◽  
Unclear Etiology ◽  
Eqtl Data

Research question: Polycystic ovary syndrome (PCOS) is a common endocrine disorder with unclear etiology. Are there any genes that are pleiotropically or potentially causally associated with PCOS? Design: We applied the summary data-based Mendelian randomization (SMR) method integrating genome-wide association study (GWAS) for PCOS and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with PCOS. We performed separate SMR analysis using eQTL data in the ovary and whole blood. Results: Although no genes showed significant pleiotropic association with PCOS after correction for multiple testing, some of the genes exhibited suggestive significance. RPS26 showed the strongest suggestive pleiotropic association with PCOS in both SMR analyses (β[SE]=0.10[0.03], PSMR=1.72*10-4 for ovary; β[SE]=0.11[0.03], PSMR=1.40*10-4 for whole blood). PM20D1 showed the second strongest suggestive pleiotropic association with PCOS in the SMR analysis using eQTL data for the whole blood, and was also among the top ten hit genes in the SMR analysis using eQTL data for the ovary. Two other genes, including CTC-457L16.2 and NEIL2, were among the top ten hit genes in both SMR analyses. Conclusion: We identified multiple genes that were potentially involved in the pathogenesis of PCOS. Our findings provided helpful leads to a better understanding of the mechanisms underlying PCOS, and revealed potential therapeutic targets for the effective treatment of PCOS.

scholarly journals Polycystic Ovary Syndrome Susceptibility Loci Inform Disease Etiological Heterogeneity

2021 ◽  
Vol 10 (12) ◽  
pp. 2688
Author(s):  
Yanfei Zhang ◽  
Vani C. Movva ◽  
Marc S. Williams ◽  
Ming Ta Michael Lee
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Strong Association ◽  
Sex Hormone Binding Globulin ◽  
Model Assessment ◽  
Ovary Syndrome ◽  
Insulin Resistant ◽  
Disease Outcomes ◽  
Unclear Etiology

Polycystic ovary syndrome (PCOS) is a complex disorder with heterogenous phenotypes and unclear etiology. A recent phenotypic clustering study identified metabolic and reproductive subtypes of PCOS. We hypothesize that the heterogeneity of PCOS manifestations reflects different mechanistic pathways and can be identified using a genetic approach. We applied k-means clustering to categorize the genome-wide significant PCOS variants into clusters based on their associations with selected quantitative traits that likely reflect PCOS etiological pathways. We evaluated the association of each cluster with PCOS-related traits and disease outcomes. We then applied Mendelian randomization to estimate the causal effects between the traits and PCOS. Three categories of variants were identified: adiposity, insulin resistant, and reproductive. Significant associations were observed for variants in the adiposity cluster with body mass index (BMI), waist circumference and breast cancer, and variants in the insulin-resistant cluster with fasting insulin, glucose values, and homeostatic model assessment of insulin resistance (HOMA-IR). Sex hormone binding globulin (SHBG) has strong association with all three clusters. Mendelian randomization suggested a causal role of BMI and SHBG on PCOS. No causal associations were observed for PCOS on disease outcomes.

scholarly journals The Association Between Genetically Predicted Systemic Inflammatory Regulators and Polycystic Ovary Syndrome: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanxiao Chen ◽  
Yaoyao Zhang ◽  
Shangwei Li ◽  
Yuanzhi Tao ◽  
Rui Gao ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genome Wide Association Study ◽  
Metabolic Diseases ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Reproductive Age ◽  
European Ancestry ◽  
Ovary Syndrome ◽  
Increased Risk

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic diseases among women of reproductive age. Inflammation may be involved in the pathogenesis of PCOS, but its exact relationship with PCOS remains unclear. Herein, we investigate the causal association between systemic inflammatory regulators and PCOS risk through a two-sample Mendelian randomization (MR) approach based on the latest and largest genome-wide association study (GWAS) of 41 systemic inflammatory regulators in 8293 Finnish participants and a GWAS meta-analysis consisting of 10,074 PCOS cases and 103,164 controls of European ancestry. Our results suggest that higher levels of IL-17 and SDF1a, as well as lower levels of SCGFb and IL-4, are associated with an increased risk of PCOS (OR = 1.794, 95% CI = 1.150 – 2.801, P = 0.010; OR = 1.563, 95% CI = 1.055 – 2.315, P = 0.026; OR = 0.838, 95% CI = 0.712 – 0.986, P = 0.034; and OR = 0.637, 95% CI = 0.413 – 0.983, P = 0.042, respectively). In addition, genetically predicted PCOS is related to increased levels of IL-2 and VEGF (OR = 1.257, 95% CI = 1.022 – 1.546, P = 0.030 and OR = 1.112, 95% CI = 1.006 – 1.229, P = 0.038, respectively). Our results indicate the essential role of cytokines in the pathogenesis of PCOS. Further studies are warranted to assess the possibility of these biomarkers as targets for PCOS prevention and treatment.

scholarly journals Hypomethylation of the LH/Choriogonadotropin Receptor Promoter Region Is a Potential Mechanism Underlying Susceptibility to Polycystic Ovary Syndrome

Endocrinology ◽  
2014 ◽  
Vol 155 (4) ◽  
pp. 1445-1452 ◽  
Author(s):  
Peng Wang ◽  
Han Zhao ◽  
Tao Li ◽  
Wei Zhang ◽  
Keliang Wu ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Promoter Region ◽  
Genome Wide Association Study ◽  
Polycystic Ovary ◽  
Methylation Status ◽  
Susceptibility Gene ◽  
Potential Mechanism ◽  
Ovary Syndrome ◽  
Cpg Sites ◽  
Flanking Regions

Our previous genome-wide association study identified LH/choriogonadotropin receptor (LHCGR) as a susceptibility gene for polycystic ovary syndrome (PCOS). The objective of this study was to determine whether the genetic or epigenetic components associated with LHCGR participate in the pathogenesis of PCOS. The exons and flanking regions of LHCGR were sequenced from 192 women with PCOS, and no novel somatic mutations were identified. In addition, the methylation statuses of 6 cytosine-phosphate-guanine (CpG) sites in the promoter region of LHCGR were measured by pyrosequencing using peripheral blood cells from 85 women with PCOS and 88 control women. We identified 2 hypomethylated sites, CpG −174 (corrected P = .018) and −111 (corrected P = .006). Bisulfite sequencing then was performed to replicate these findings and detect additional CpG sites in the promoter. CpG +17 was significantly hypomethylated in women with PCOS (corrected P = .02). Methylation statuses were further evaluated using granulosa cells (GCs), and the region described was hypomethylated as a whole (P = .004) with 8 significantly hypomethylated sites (CpG −174, −148, −61, −43, −8, +10, +17, and +20). Transcription of LHCGR was elevated in women with PCOS compared with that in control women (P < .01). These findings were consistent with the decreased LHCGR methylation status associated with PCOS. The tendency of LHCGR to be hypomethylated across different tissues and its corresponding expression level suggest that hypomethylation of LHCGR is a potential mechanism underlying susceptibility to PCOS. Further studies are needed to evaluate whether a causal relationship exists between LHCGR methylation status and PCOS.

Maternal polycystic ovary syndrome and offspring birth weight: a Mendelian randomization study

2021 ◽  
Author(s):  
Yuexin Gan ◽  
Donghao Lu ◽  
Chonghuai Yan ◽  
Jun Zhang ◽  
Jian Zhao
Keyword(s):  
Birth Weight ◽  
Polycystic Ovary Syndrome ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Ovary Syndrome ◽  
Genetic Instruments

Abstract Background Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain. Objective We conducted a two-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW. Methods We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in the genome-wide association study (GWAS) meta-analysis including 10,074 PCOS cases and 103,164 controls of European ancestry from seven cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics (EGG) consortium (n = 406,063 European-ancestry individuals) using the weighted linear model (WLM), an approximation method of structural equation model (SEM), which separated maternal genetic effects from fetal genetic effects. We used a two-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results. Results We found little evidence for a causal effect of maternal PCOS on offspring BW (-6.1 g, 95% confidence interval [CI]: -16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses. Conclusion Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.

scholarly journals Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhikun Yang ◽  
Jingyun Yang ◽  
Di Liu ◽  
Weihong Yu
Keyword(s):  
Multiple Testing ◽  
Central Corneal Thickness ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Open Angle Glaucoma ◽  
East Asian ◽  
Corneal Thickness ◽  
European Ancestry ◽  
Genome Wide ◽  
Eqtl Data

Abstract Objective To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT). Methods We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately. Results We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR = 4.15 × 10− 12), PTGDS (ILMN_1664464; PSMR = 6.88 × 10− 9) and C9orf142 (ILMN_1761138; PSMR = 8.09 × 10− 9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; PSMR = 5.89 × 10− 9), LCNL1 (ENSG00000214402.6; PSMR = 5.67 × 10− 8), and PTGDS (ENSG00000107317.7; PSMR = 1.92 × 10− 7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing. Conclusion We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.

scholarly journals Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Milana Kokosar ◽  
Anna Benrick ◽  
Alexander Perfilyev ◽  
Romina Fornes ◽  
Emma Nilsson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Multiple Testing ◽  
Polycystic Ovary ◽  
Differentially Expressed Gene ◽  
Human Adipose Tissue ◽  
Differentially Expressed ◽  
Ovary Syndrome ◽  
Unique Genes

Abstract Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed “gene-CpG” probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease.

Sign in / Sign up

Export Citation Format

Share Document