Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry
Authors: Burns Kharis , Mullin Benjamin H. , Moolhuijsen Loes M. E. , Laisk Triin , Tyrmi Jaakko S. , Cui Jinrui , Actkins Ky’Era V. , Louwers Yvonne V. ,   Estonian Biobank Research Team, Metspalu Andres , Milani Lili , Esko Tõnu , Nelis Mari , Hudjashov Georgi , Davis Lea K. , Dudbridge Frank , Azziz Ricardo , Goodarzi Mark O. , Laivuori Hannele , Mägi Reedik , Visser Jenny A. , Laven Joop S. E. , Wilson Scott G. ,   FinnGen,   International PCOS Consortium, Karaderi Tugce , Jones Michelle R. , Meun Cindy , He Chunyan , Drong Alex , Kraft Peter , Lin Nan , Huang Hongyan , Broer Linda , Saxena Richa , Metspalu Andres , Milani Lili , Esko Tõnu , Nelis Mari , Hudjashov Georgi , Urbanek Margrit , Hayes M. Geoffrey , Thorleifsson Gudmar , Fernandez-Tajes Juan , Mahajan Anubha , Spector Timothy D. , Obermayer-Pietsch Barbara , Uitterlinden André G. , Anttila Verneri , Neale Benjamin M. , Jarvelin Marjo-Riitta , Daly Mark , Fauser Bart , Kowalska Irina , Andersen Marianne , Ong Ken , Stener-Victorin Elisabet , Ehrmann David , Legro Richard S. , Salumets Andres , McCarthy Mark I. , Morin-Papunen Laure , Thorsteinsdottir Unnur , Stefansson Kari ,   The Maziko trial team, Styrkarsdottir Unnur , Perry John R. B. , Dunaif Andrea , Franks Steve , Lindgren Cecilia M. , Welt Corrine K. , Day Felix R. , Stuckey Bronwyn G. A. 
Published: February 2024

Abstract
Background
Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.

Results
The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10–12) and rs2228260 within XBP1 (P = 3.68 × 10–8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10–6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10–9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10–6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.

Conclusions
Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.