Polycystic ovary syndrome (PCOS) is a complex, multi-system, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive-aged women. While insulin resistance (IR) is not a diagnostic feature, it is widespread in women with PCOS, and often more severe than in women of similar age and BMI. Conversely, women with rare Mendelian disorders of IR also present with features of PCOS. We hypothesize that PCOS is driven by underlying IR, which can be evaluated through a genetic approach. We curated and stratified 310 genes related to three mechanisms of IR using molecular and clinical criteria. We evaluated protein-altering genetic variation in 102 insulin signaling genes, 29 obesity genes, and 22 dyslipidemia genes from whole-exome sequencing data from 675 PCOS patients. 40 insulin signaling genes, 12 obesity genes, and 10 dyslipidemia genes were significantly enriched for protein-altering variation in PCOS cases compared to healthy population controls. Variants in these 62 significantly enriched genes affected 51% of PCOS cases in our study cohort. The 15 highest ranked genes were selected for follow-up: LMNA, LEPR, KCNJ11, BSCL2, ACACA, NTRK2, GCK, ABCC8, SLC2A2, POMC, MC4R, TBC1D4, INSR, NR0B2, and GCKR. 50% of variants identified in these 15 genes were pathogenic, 35% were likely pathogenic, and only 15% were variants of uncertain significance. These findings support IR as a central pathway in PCOS. Furthermore, this study demonstrates that a candidate pathway approach with sufficient pre-processing can successfully identify functionally relevant variants and genes underlying complex traits.

RB, CP, ZCM, MGH, CKW, and MU have nothing to declare. RSL consults for Bayer, Eli Lilly, Celmatix, and Organon which may have interests in PCOS. ARK owns stock in Merck, a pharmaceutical company.

This study was supported by US National Institutes of Health (NIH) grants R01 HD057450 (MU), P50 HD044405 (MU), R01 HD100630 (MU), R01 HD056510 (RSL), R01 HD065029 (CKW) and T32 HD094699 (RB). Additional funding was provided by the Androgen Excess & PCOS Foundation Waterloo Award (RB). Partial funding for the clinical studies was provided by UL1 TR000150, UL1 RR033184, UL1 TR000430 and UL1 RR025758 from the National Center for Advancing Translational Sciences. Some hormone assays were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core that is supported by U54 HD28934 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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IRB of Massachusetts General Hospital (MGH) gave ethical approval for this work IRB of University of Utah gave ethics approval for this work IRB of Pennsylvania State College of Medicine gave ethics approval for this work

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