Phenotypes Associated With Polycystic Ovary Syndrome Risk Variants

Polycystic ovary syndrome (PCOS) affects 10% of women of reproductive age. The genetic architecture of the disease is emerging, but there is little data exploring the effect of genetic risk on clinical presentation.

We hypothesized that genetic risk loci would influence measurable phenotypic traits.

This retrospective cohort study, conducted at an academic medical center, included women of European ancestry with PCOS (n = 404), as diagnosed by the National Institutes of Health criteria, and controls with regular menses and no hyperandrogenism (n = 408). We identified association between genetic risk variants and measured phenotypic traits using linear regression.

In a combined analysis of cases and controls, 2 variants in loci containing the genes PRSS23 (P < .001) and FSHB (P < .001) were associated with gonadotropin levels. Two variants in loci containing NEIL2/GATA4 (P = .002) and CYP3 (P < .001) were associated with androgen levels. Three variants in loci containing SHBG (P = .001), ZBTB16 (P < .001), and CYP3 (P < .001) were associated with ovarian morphology. One variant in the locus containing FTO (P = .001) was associated with hip circumference and was influenced by body mass index.

These results demonstrate that PCOS genetic risk variants may influence hormone levels and ovarian morphology and increase the risk of obesity. Increased genetic risk for PCOS appears to drive traits that underly the classical clinical presentation of PCOS.