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Characterization of Rare Genetic Variation in Polycystic Ovary Syndrome

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Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 1 in 10 reproductive-age women and remains the leading cause of female factor infertility among women of childbearing age. PCOS presents with features of hyperandrogenism, irregular menses and polycystic ovaries. Twin and family studies have demonstrated high heritability estimates for PCOS. Consequently, a number of common genetic PCOS susceptibility loci have been reproducibly mapped using family-based association tests or GWAS. However, taken together, these loci only account for a small fraction of PCOS heritability, analogous to findings in other complex traits/diseases. One hypothesis for the observed deficit in heritability is that uncommon or rare genetic variants with greater phenotypic effects contribute to disease pathogenesis. We tested this hypothesis using an unbiased whole genome sequencing (WGS) approach followed by targeted resequencing of a gene panel including 11 PCOS candidates in a case/control cohort. Subsequent in silico analyses yielded PCOS-associated rare genetic variants, both in coding and noncoding regions of the genome. Two of the 11 panel genes included anti-Müllerian hormone (AMH) and its specific type II receptor (AMHR2). Women affected with PCOS often have elevated levels of AMH. In the ovary AMH inhibits follicle maturation, thus the elevated AMH levels seen in women with PCOS are consistent with the observed arrested folliculogenesis. Paradoxically, AMH also inhibits androgen production through transcriptional repression of CYP17, a rate-limiting enzyme in steroidogenesis. This suggests a loss of AMH function in PCOS, a phenotype of androgen excess. Identified coding and select noncoding variants of AMH and AMHR2 were studied to determine their functional impact on signaling ability. Using dual luciferase reporter assays and quantitative real-time PCR, we identified a total of 37 PCOS-specific variants in AMH and AMHR2 that displayed a significant reduction in activity. Collectively, 50 PCOS cases harbored functionally validated pathogenic variants, equating to 7.1% (50/700) of our case cohort. None of the variants observed in control women had impaired signaling activity. Our findings are the first to identify and functionally validate rare genetic variants associated with a common PCOS phenotype and suggest a previously unrecognized mechanism for the role of AMH in PCOS: decreased AMH bioactivity. Given that PCOS is a complex disorder with a heterogeneous presentation, several genes and pathways likely lead to various PCOS phenotypes. Analyses of targeted resequencing data also identified predicted deleterious missense variants, specific to PCOS cases, mapping to the LMNA and INSR genes that encode the lamin A/C and insulin receptor, respectively. Mutations in these genes cause disorders associated with extreme phenotypes of PCOS. Our results indicate that rare variants in LMNA and INSR also account for a subgroup of PCOS-affected women.

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  • 04/09/2019
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