Journal of Clinical Medicine Review The Genetics of Polycystic Ovary Syndrome: An Overview of Candidate Gene Systematic Reviews and Genome-Wide Association Studies Danielle Hiam 1, Alba Moreno-Asso 1, Helena J. Teede 2 , Joop S.E. Laven 3, Nigel K. Stepto 1,2,4 , Lisa J. Moran 2 and Melanie Gibson-Helm 2,* 1 Institute of Health and Sport, Victoria University, Melbourne 3011, Australia; [email protected] (D.H.); [email protected] (A.M.-A.); [email protected] (N.K.S.) 2 Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne 3168, Australia; [email protected] (H.J.T.); [email protected] (L.J.M.) 3 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands; [email protected] 4 Australian Institute of Musculoskeletal Science (AIMSS), Victoria University, St Albans 3021, Australia * Correspondence: [email protected] Received: 9 September 2019; Accepted: 30 September 2019; Published: 3 October 2019 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: Polycystic Ovary Syndrome; genetics; genetic association studies; Systematic Review; Overview of Systematic Reviews 1. Introduction Polycystic ovary syndrome (PCOS) is a major public health concern affecting 6–10% of reproductive aged women [1]. PCOS is exacerbated by obesity and has significant metabolic, reproductive, and psychological features, including an increased risk of Type 2 Diabetes Mellitus (T2DM) with an earlier age of onset, subfertility, and an increased risk of depression and anxiety symptoms [2–4]. At present, the internationally accepted criteria for diagnosis of PCOS is the revised Rotterdam criteria [5], which requires exclusion of other causes of hyperandrogenism, like adrenal or pituitary dysfunction, and presence of two of the following three characteristics: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound. The Rotterdam J. Clin. Med. 2019, 8, 1606; doi:10.3390/jcm8101606 www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, 1606 2 of 17 J. Clin. Med. 2019, 8, 1606 2 of 17 criteria yields four phenotypes of PCOS, and there is evidence that the different PCOS phenotypes have ultrasound. The Rotterdam criteria yields four phenotypes of PCOS, and there is evidence that the varying degrees of adiposity, and may differ in metabolic and reproductive profiles [6]. The proposed different PCOS phenotypes have varying degrees of adiposity, and may differ in metabolic and pathophysiology of PCOS is a synergistic relationship between perturbed gonadotrophin releasing reproductive profiles [6]. The proposed pathophysiology of PCOS is a synergistic relationship hormones (GnRH) pulsatility and hyperandrogenism probably accompanied by hyperinsulinemia, between perturbed gonadotrophin releasing hormones (GnRH) pulsatility and hyperandrogenism insulin resistance, and inflammation. However, the nuances of these relationships are yet to be fully probably accompanied by hyperinsulinemia, insulin resistance, and inflammation. However, the elucidated (Figure1)[7–9]. nuances of these relationships are yet to be fully elucidated (Figure 1) [7–9]. Figure 1.1. Proposed pathophysiology and features of PolycysticPolycystic Ovary SyndromeSyndrome (PCOS).(PCOS). AdaptedAdapted and reproduced with permission [[2]2].. CV, cardiovascular;cardiovascular; IGT, impairedimpaired glucoseglucose tolerance; TD2M, type 22 diabetes.diabetes. In addition,addition, PCOS PCOS pathophysiology pathophysiology appears appears to have to a have polygenic a polygenic predisposition predisposition that is exacerbated that is byexacerbated environmental by environmental factors, especially factors, obesity especially [2]. The obesity polygenic [2]. The predisposition polygenic predisposition is well documented is well withdocumented familial clusteringwith familial of PCOS clustering symptoms, of PCOS providing symptoms, evidence providing for a genetic evidence contribution for a genetic to the pathophysiologycontribution to the [10 ].pathophysiology Both female and male[10]. familyBoth female members and of womenmale family diagnosed members with PCOSof women share commondiagnosed characteristics with PCOS ofshare the syndrome.common characteristics Moreover, they of seem the syndrome. to be more proneMoreover, to develop they seem T2DM to and be metabolicmore prone syndrome to develop [11]. T2DM Finally, and mono- metabolic and dizygotic syndrome twin studies[11]. Finally, have demonstrated mono- and dizygotic the heritability twin ofstudies PCOS have to be demonstrated approximately the 70% heritability [12]. of PCOS to be approximately 70% [12]. Two complementarycomplementary types of genetic studies are Genome Wide Association Studies (GWAS) and candidate gene studies. GWAS looklook forfor associationsassociations betweenbetween commoncommon geneticgenetic polymorphismspolymorphisms and the trait or or disease disease without without a a predefined predefined hypothes hypothesisis about about the the possible possible role role of ofgenetic genetic variants variants in inthe the pathophysiology. pathophysiology. However, However, a acommon common misunderstanding misunderstanding about about GWAS GWAS is is that that they identifyidentify specificspecific genes. They merely provide information aboutabout a genetic region (gene loci) that is significantly significantly associated with the trait. On one hand, the identifi identifieded gene loci might be directly involved in gene function if located in or near a gene,gene, or theythey might have a regulatory function for genes up- or downstream. Hence, genetic loci detected by GWAS provide ideal a priori candidate genes that are located withinwithin these these loci loci to investigate.to investigate. GWAS GWAS have beenhave conductedbeen conducted in Chinese, in Chinese, Korean, andKorean, European and cohorts,European and cohorts, have identifiedand have upidentified to 19 distinct up to 19 genetic distinct loci genetic in, ornear, loci in, known or near, genes known that aregenes associated that are withassociated PCOS with [13– 19PCOS]. Candidate [13–19]. geneCandidate studies gene are particularlystudies are usefulparticularly to validate useful and to validate decipher and the functionaldecipher the impact functional of gene impact loci identified of gene byloci GWAS identi tofied contextualise by GWAS clinicalto contextualise relevance clinical [20]. A multituderelevance of[20]. candidate A multitude gene studies of candidate have been gene conducted studies inhave PCOS, been identifying conducted single in nucleotidePCOS, identifying polymorphisms single (SNPs)nucleotide that polymorphisms may contribute (SNPs) to the geneticthat may basis contribute of PCOS to [14 the]. Thesegenetic studies basis of provide PCOS an[14]. eff ectiveThese approachstudies provide for detecting an effective genetics approach variants for that detecting are either genetics causative variants or belong that are to aeither shared causative haplotype or thatbelong is causativeto a shared [21 haplotype–23]. However, that is candidate causative gene[21–23]. studies However, have manycandidate common gene limitations,studies have such many as common limitations, such as sample size and selection bias from confounding variables such as J. Clin. Med. 2019, 8, 1606 3 of 17 sample size and selection bias from confounding variables such as ancestry, diagnostic criteria, BMI, and source of participants, which can limit statistical power and result in different findings [24,25]. In all fields of science, systematic evaluations are crucial for establishing the consistency and significance of the current evidence base [24]. Such evaluations may take the form of systematic reviews of individual studies or overviews of systematic reviews. 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