Moolhuijsen LME., Zhu J., Mullin BH., Pujol-Gualdo N., Actkins KV., Mack JA., Rao H., Trivedi B., Kentistou KA., Zhao Y., Westergaard D., Tyrmi JS., Thorleifsson G., Zhang Y., Wittemans L., DeVries A., Brewer K., Sisk R., Danning R., Preuss MH., Jones MR., Ruth KS., Andersen M., Azziz R., Banasik K., Boehnke M., Broer L., Brunak S., Chan Y-M., Chasman DI., Daly M., Ehrmann DA., Fauser BC., Fritsche LG., Hayes MG., He C., Huang H., Kowalska I., Kraft P., Legro RS., Lin N., Loos RJ., Louwers YV., Magi R., McCarthy MI., Morin-Papunen L., Morrison JV., Morton C., Nadkarni GN., Neale BM., Nielsen HS., Nyegaard M., Ostrowski SR., Pedersen OBV., Sørensen E., Mikkelsen C., Erikstrup C., Kaspersen KA., Bruun MT., Aagaard B., Ullum H., Obermayer-Pietsch B., Palotie A., Reeve MP., Salumets A., Saxena R., Spector TD., Stuckey BGA., Thorsteinsdottir U., Uitterlinden AG., Urbanek M., Zöllner S., Genes and Health Research Team ., DBDS Genomic Consortium ., 23andMe Research Team ., van Heel DA., Hirschhorn JN., Stefansson K., Perry JRB., Styrkarsdottir U., Wilson SG., Piltonen T., Laisk T., Jarvelin M-R., Burns K., Justice AE., Laivuori H., Ong KK., Goodarzi MO., Davis LK., Dunaif A., Lindgren CM., Laven JSE., Franks S., Visser JA., Welt CK., Karaderi T., Day FR.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.

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