Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.
Day Felix,Karaderi Tugce,Jones Michelle R,Meun Cindy,He Chunyan,Drong Alex,Kraft Peter,Lin Nan,Huang Hongyan,Broer Linda,Magi Reedik,Saxena Richa,Laisk Triin,Urbanek Margrit,Hayes M Geoffrey,Thorleifsson Gudmar,Fernandez-Tajes Juan,Mahajan Anubha,Mullin Benjamin H,Stuckey Bronwyn G A,Spector Timothy D,Wilson Scott G,Goodarzi Mark O,Davis Lea,Obermayer-Pietsch Barbara,Uitterlinden André G,Anttila Verneri,Neale Benjamin M,Jarvelin Marjo-Riitta,Fauser Bart,Kowalska Irina,Visser Jenny A,Andersen Marianne,Ong Ken,Stener-Victorin Elisabet,Ehrmann David,Legro Richard S,Salumets Andres,McCarthy Mark I,Morin-Papunen Laure,Thorsteinsdottir Unnur,Stefansson Kari, ,Styrkarsdottir Unnur,Perry John R B,Dunaif Andrea,Laven Joop,Franks Steve,Lindgren Cecilia M,Welt Corrine K
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
Abdominal adiposity and the polycystic ovary syndrome.
Escobar-Morreale Héctor F,San Millán José L
Trends in endocrinology and metabolism: TEM
Abdominal adiposity, overweightness and obesity are frequently present in patients with polycystic ovary syndrome (PCOS). A large body of evidence suggests that abdominal adiposity and the resulting insulin resistance contribute to ovarian and, possibly, adrenal hyperandrogenism. However, androgen excess itself might also contribute to abdominal fat deposition in hyperandrogenic women. Recent genomic and proteomic analyses of visceral fat from PCOS patients have detected differences in gene expression and protein content compared with those of non-hyperandrogenic women. Here we review the existing evidence for a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals in PCOS patients.
Functional genomics of PCOS: from GWAS to molecular mechanisms.
McAllister Jan M,Legro Richard S,Modi Bhavi P,Strauss Jerome F
Trends in endocrinology and metabolism: TEM
Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. PCOS has a strong heritable component based on familial clustering and twin studies. Genome-wide association studies (GWAS) identified several PCOS candidate loci including LHCGR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3. We review the functional roles of strong PCOS candidate loci focusing on FSHR, LHCGR, INSR, and DENND1A. We propose that these candidates comprise a hierarchical signaling network by which DENND1A, LHCGR, INSR, RAB5B, adapter proteins, and associated downstream signaling cascades converge to regulate theca cell androgen biosynthesis. Future elucidation of the functional gene networks predicted by the PCOS GWAS will result in new diagnostic and therapeutic approaches for women with PCOS.