Loci on chromosome 12q13.2 encompassing ERBB3, PA2G4 and RAB5B are associated with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia of ovarian theca cell origin. Here we report the significant association of 15 single nucleotide polymorphisms (SNPs), identified by whole exome sequencing (WES). DNA was isolated from well-characterized theca cell preparations from women of European ancestry with PCOS (N=9) and elevated androgen production in vitro and from normal ovulatory women (N=7). Of the SNPs, 10 are located within 150 kb on chromosome 12q13.2. This region contains three plausible PCOS candidate genes ( ERBB3/PA2G4/RAB5B ), two of which ( ERBB3 and RAB5B ) have been identified in GWAS of PCOS. None of the SNPs individually had a significant association with PCOS or in vivo androgen levels when evaluated in an independent cohort (n=318) of families with one or more daughters with PCOS, but a haplotype consisting of the minor alleles of three of the SNPS (rs773121, rs773123 and rs812826) was found preferentially in women with PCOS and elevated androgen levels (p=0.0583). Moreover, the three minor alleles in this haplotype were significantly associated with anti-Mullerian Hormone (AMH) levels, a marker of follicular reserve and follicular maturation. Two of the three SNP minor alleles are predicted to have significant functional consequences (rs773123 a missense SNP in ERBB3 , and rs812826, a SNP in the PA2G4 promoter). Notably, PA2G4 encodes a protein that interacts with the ERBB3 cytoplasmic domain, which is also the domain where the missense variant resides. These findings provide support for the contribution and probable functional significance of loci on chromosome 12q13.2 to the pathophysiology underlying PCOS. Author Summary Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age. We identified 15 single nucleotide polymorphisms (SNPs) associated with androgen production in theca cells from normal ovulatory women and women with PCOS. Of these SNPs, 10 are within a 150 kbp region of chromosome 12 including 9 that form a haplotype. This region contains three PCOS candidate genes ( ERBB3/PA2G4/RAB5B ). These SNPs were further examined in an independent cohort of families with one or more daughters with PCOS. A haplotype consisting of the minor alleles of three of the SNPS was found preferentially in women with PCOS. Furthermore, the three minor alleles in this haplotype were significantly associated with anti-Mullerian Hormone (AMH) levels, a marker of follicular reserve and maturation. Two SNPs in the chromosome 12 haplotype were likely to have functional consequences based on genomic context, suggesting that they affect ERBB3 and PA2G4 interactions or PA2G4 expression.