Candidate pathway genetic analysis of PCOS
M. Urbanek1, O. Garcia1, T. Woodruff1, R. Legro2, A. Dunaif1 & P. Mutharasan1
Polycystic ovary syndrome (PCOS) is a characterized by hyperandrogenism and irregular menses and is associated with insulin resistance, type 2 diabetes and obesity. While there is a strong genetic component to PCOS, candidate gene analyses and genome wide association studies (GWAS) have identified only a handful of replicated PCOS susceptibility loci. Therefore, we employed a candidate pathway approach to identify additional PCOS susceptibility loci. This approach is more comprehensive than single candidate gene analyses but also more targeted than GWAS, there is a reduced penalty for multiple testing allowing the detection of genes with smaller effect sizes. We tested for association between PCOS and 4930 SNPs mapping to 299 genes belonging to four pathways (ovarian rigidity (117 genes), TGF β signaling (77 genes), insulin resistance, diabetes and obesity (28 genes), and inflammation (77)) in a European ancestry cohort of 931 women with PCOS according to NIH criteria and 957 control women. After adjusting for population substructure and body mass index, the strongest evidence for association was with genes previously implicated in obesity, diabetes or insulin resistance (39% of genes with P values <0.01) and genes whose expression is altered in a murine model of ovarian rigidity (22% of genes with P values <0.01). The five genes with the strongest evidence for association with were RAMP1 (receptor G protein-coupled activity modifying protein 1; rs13405506 allele T, odds ratio=0.57, P value=0.00010), FTO (fat mass and obesity associated; rs8056199 allele A, odds ratio=1.47, P value=0.00015), ADAMTS19 (ADAM metallopeptidase with thrombospondin type 1 motif, 19; rs246246 allele G, odds ratio=0.56, P value=0.00035), TBC1D4 (TBC1 domain family, member 4; rs9318332 allele C, odds ratio=1.43, P value=0.00054), and SERPINA12 (serpin peptidase inhibitor, clade A, member 12; rs12433377 allele G, odds ratio=1.63, P value=0.00056). This study provides convincing evidence that the ovarian and metabolic environment contribute to the PCOS phenotype.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.