Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

• Main Authors: Burns, Kharis, Mullin, Benjamin H., Moolhuijsen, Loes M.E., Laisk, Triin, Tyrmi, Jaakko S., Cui, Jinrui, Actkins, Ky’Era V., Louwers, Yvonne V., Davis, Lea K., Dudbridge, Frank, Azziz, Ricardo, Goodarzi, Mark O., Laivuori, Hannele, Mägi, Reedik, Visser, Jenny A., Laven, Joop S.E., Wilson, Scott G., Day, Felix R., Stuckey, Bronwyn G.A.
• Other Authors: HUS Gynecology and Obstetrics, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, Department of Medical and Clinical Genetics, Department of Obstetrics and Gynecology, Helsinki Institute of Life Science HiLIFE
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2024
• Subjects: BMI; Body mass index; GWAS; Lean; Meta-analysis; Obese; PCOS; Polycystic ovary syndrome; Medical biotechnology; Genetics; developmental biology; physiology; Arctic
• Online Access: http://hdl.handle.net/10138/574238

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 ...