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.
Highlights
Polycystic ovary syndrome (PCOS) is a major public health concern affecting 6–10% of reproductive aged women [1]
We found little overlap between gene loci identified from Genome-wide association studies (GWAS) and those identified from the candidate gene systematic reviews
Future genetic studies should consider performing Phenome-Wide Association Studies (PheWAS) which examine many different phenotypes to see which, if any, are associated with a given genetic variant [78]. The findings of this overview provide potential pathways that could be used in PheWAS to determine the functional relevance of the identified genes, and secondly, to explore associations between genetic polymorphisms and different PCOS phenotypes. The importance of this has been recently highlighted in a GWAS meta-analysis where it was identified that the SNP rs804279 in the GATA4/NEIL2 gene loci was strongly associated with the NIH diagnostic criteria, which encompasses only hyperandrogenic PCOS phenotypes, compared to the Rotterdam criteria, which encompasses the non-hyperandrogenic PCOS phenotypes [17]
Summary
Polycystic ovary syndrome (PCOS) is a major public health concern affecting 6–10% of reproductive aged women [1]. OHwoewverv,era, acocmommmononmmisiusnudnedresrtsatnadnidnigngabaobuotutGGWWAASSisis tthhaatt they identify specifificc geenneess They merely provide information about a genetic region (gene loci) that is signiffiicantly associated with the trait. In all fields of science, systematic evaluations are crucial for establishing the consistency and significance of the current evidence base [24]. An overview of systematic reviews aims to assess the methodological quality of systematic reviews on a given topic and the consistency of evidence contained in them [26] The aim of this overview was to systematically evaluate the current evidence regarding the genetics of PCOS from candidate gene systematic reviews and GWAS. We explored the methodological quality of the systematic reviews to identify how future genetic studies can align the findings of candidate gene and GWAS studies by validating gene loci. A comprehensive understanding of the current evidence and its limitations is necessary to improve our understanding of the biological origins of PCOS
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