The Genetics of Polycystic Ovary Syndrome: An Overview of Candidate Gene Systematic Reviews and Genome-Wide Association Studies

Abstract

Polycystic Ovary Syndrome (PCOS) is a complex condition with mechanisms likely to involve the interaction between genetics and lifestyle. Familial clustering of PCOS symptoms is well documented, providing evidence for a genetic contribution to the condition. This overview aims firstly to systematically summarise the current literature surrounding genetics and PCOS, and secondly, to assess the methodological quality of current systematic reviews and identify limitations. Four databases were searched to identify candidate gene systematic reviews, and quality was assessed with the AMSTAR tool. Genome-wide association studies (GWAS) were identified by a semi structured literature search. Of the candidate gene systematic reviews, 17 were of high to moderate quality and four were of low quality. A total of 19 gene loci have been associated with risk of PCOS in GWAS, and 11 of these have been replicated across two different ancestries. Gene loci were located in the neuroendocrine, metabolic, and reproductive pathways. Overall, the gene loci with the most robust findings were THADA, FSHR, INS-VNTR, and DENND1A, that now require validation. This overview also identified limitations of the current literature and important methodological considerations for future genetic studies. Much work remains to identify causal variants and functional relevance of genes associated with PCOS.

Keywords: Overview of Systematic Reviews; Polycystic Ovary Syndrome; Systematic Review; genetic association studies; genetics.

Figure 1

Proposed pathophysiology and features of Polycystic Ovary Syndrome (PCOS). Adapted and reproduced with permission [2]. CV, cardiovascular; IGT, impaired glucose tolerance; TD2M, type 2 diabetes.

Figure 2

Identification and selection of systematic reviews of genetics and polycystic ovary syndrome.

Figure 3

Forest plots representing the association between metabolic SNPs and PCOS under the allele model. (A) Insulin receptor; (B) Insulin gene variable number of tandem repeats (INS-VNTR); (C) Insulin Receptor Substrate-1 (IRS-1); (D) Insulin Receptor Substrate-2 (IRS-2); (E) Transcription Factor 7-Like 2 (TCF7L2); (F) Calpain-10; (G) Adiponectin; (H) Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1); (I) Cytochrome P450 Family 11 Subfamily A Member 1 (CYP11A1); (J) DENN domain containing 1A (DENND1A); (K) Paraoxonase 1 (PON1). The circle represents the odds ratio (OR) and the horizontal lines are the 95% confidence intervals (CI).

Figure 4

Forest plots representing the association between metabolic SNPs and PCOS under the allele model. (A) Follicle Stimulating Hormone Receptor (FSHR); (B) Androgen Receptor (AR); (C) Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17); (D) Anti-müllerian hormone (AMH); Anti-müllerian hormone receptor II (AMHRII). The circle represents the odds ratio (OR) and the horizontal lines are the 95% confidence intervals (CI).

Figure 5

Forest plots representing the association between metabolic SNPs and PCOS under the allele model. (A) TNF-α, Tumor Necrosis Factor-Alpha; (B) IL, Interleukin. The circle represents the odds ratio (OR) and the horizontal lines are the 95% confidence intervals (CI).