Genome-wide association study (GWAS) identified PCOS susceptibility variants and replicates reported risk variants.

BACKGROUND: Genetic predisposition and environmental factors are considered risk factors for polycystic ovary syndrome (PCOS). Genome-wide association studies (GWAS) have been reported from various subpopulations to evaluate SNPs associated with PCOS risk. No PCOS-associated GWAS study has been reported from India so far. PURPOSE: The current study was conducted to identify the PCOS-susceptible loci among the North Indian population and to validate the significant loci reported by previous GWAS studies. METHODS: A total of 272 participants with 134 PCOS patients and 138 age-matched healthy controls were recruited. Genomic DNA was isolated and genotyped by using Infinium Global Screening Array v3.0 microchip considering HWE 10e-5 statistically significant. RESULTS: A total of fifteen markers have been identified as candidate PCOS risk factors. Only two SNPs, namely rs17186366 and rs11171739 have been identified through replication analysis while comparing the previously reported PCOS GWAS data. In-silico analysis was performed to study the functional impact of identified significant genes for gene ontology, pathways related to gene set, and cluster analysis to determine protein-protein interaction among genes or gene products. CONCLUSION: The study suggests that multiple variants play an important role in PCOS pathogenesis and emphasizes the importance of further genetic studies among Indian subpopulations. The study also validates two previously reported SNPs in the Indian population. What this study adds to clinical work Study summarizes the importance of candidate gene markers validated by replication and in-silico functional study, significantly involved in PCOS pathogenesis in the studied population. These markers can be used in the future as diagnostic markers for clinical phenotype identification.

Investigation of the Association of Serum Trace Elements Concentrations and Serum Biochemical Parameters with the Risk of Polycystic Ovary Syndrome: a Case-Control Study.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinological syndrome characterized by hyperandrogenism of ovarian origin and is often considered a predisposing factor for metabolic disorders. The objective of the study was to investigate serum levels of (a) trace elements (copper (Cu), zinc (Zn), magnesium (Mg), selenium (Se), iron (Fe), chromium (Cr), and manganese (Mn)); and (b) biochemical parameters (glucose, cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), albumin, total protein, creatinine, and C-reactive protein (CRP) with risk of PCOS. Another objective was to explore the relationship between serum trace elements and biochemical variables. Serum trace elements were estimated by inductively coupled plasma mass spectrometry (ICP-MS) and biochemical parameters were estimated by colorimetric methods in 99 PCOS cases and 82 controls. Linear and non-linear associations of serum variables with PCOS risk were studied under logistic, probit, GAM, and BKMR model. Statistical analyses were performed using IBM SPSS 22.0 and R package version 4.2.1. All studied serum trace elements (except Zn) are significantly associated with PCOS. Combined effect analysis revealed Mg-Se and Fe-Cu association with PCOS risk. A significant association of cholesterol, HDL-C, LDL-C, CRP, and albumin was observed. Furthermore, linear regression analysis suggests an association between Mg-Cu and Mg-Fe-Mn with HDL-C; Fe and Cr-Cu with albumin; and Cu-Se with cholesterol and LDL-C both.

Genetic Variants of Steroidogenesis and Gonadotropin Pathways and Polycystic Ovary Syndrome Susceptibility: A Systematic Review and Meta-analysis.

Genetic variants are predisposing factors to polycystic ovary syndrome (PCOS), a multifactorial condition that often gets triggered due to various environmental factors. The study investigates the association of the variants of genes that are involved in the steroidogenesis pathway or gonadotropin pathway with the risk of PCOS. Appropriate keywords for predetermined genes were used to search in PubMed, Google Scholar, Science Direct, and Central Cochrane Library up to January 11, 2023. PROSPERO (CRD42022275425). Inclusion criteria: (a) case-control study; (b) genotype or allelic data. Exclusion criteria were: (a) duplicate studies; (b) clinical trials, systematic reviews, meta-analysis or conference abstract, case reports; (c) other than the English language; (d) having insufficient data; e) genetic variants for which meta-analysis has been reported recently and does not have a scope of the update. Various genetic models were applied as per data availability. Overall 12 variants of 7 genes were selected for the analysis. Relevant data were extracted from 47 studies which include 10,584 PCOS subjects and 16,150 healthy controls. Meta-analysis indicates a significant association between TOX3 rs4784165 [ORs = 1.08, 95% CI (1.00-1.16)], HMGA2 rs2272046 [ORs = 2.73, 95% CI (1.97-3.78)], YAP1 rs1894116 [OR = 1.22, 95% CI (1.13-1.33)] and increased risk of PCOS. Whereas FSHR rs2268361 [ORs = 0.84, 95% CI (0.78-0.89)] is associated with decreased PCOS risk. When sensitivity analysis was carried out, the association became significant for CYP19 rs700519 and FSHR rs6165 under an additive model. In addition, C9Orf3 rs3802457 became significantly associated with decreased PCOS risk with the removal of one study. Insignificant association was observed for CYP19A (rs2470152), FSHR (rs2349415, rs6166), C9Orf3 (rs4385527), GnRH1 (rs6185) and risk of PCOS. Our findings suggest association of CYP19A (rs700519), TOX3 (rs4784165), HMGA2 (rs2272046), FSHR (rs6165, rs2268361), C9orf3 (rs3802457), and YAP1 (rs1894116) with risk for PCOS.