Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

Abstract

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Fig 1. Manhattan plot showing results of meta-analysis for PCOS status, adjusting for age.

The inverse log10 of the p value (-log10(p)) is plotted on the Y axis. The green dashed line designates the minimum p value for genome-wide significance (<5.0 x 10⁻⁸). Genome wide significant loci are denoted with a label showing the nearest gene to the index SNP at each locus. SNPs with p values ≤1.0x10^-2 are not depicted.

Fig 2. Odds ratio of polycystic ovary syndrome (PCOS) as a function of diagnostic criteria applied.

The Y-axis specifies the diagnostic criteria and the X-axis indicates the odds ratio (OR) and 95% confidence intervals (CI) for PCOS (black circle and horizontal error bars). Data derived as follows: NIH = groups recruiting only NIH diagnostic criteria; NonNIH_Rotterdam = Rotterdam diagnostic criteria excluding the subset fulfilling NIH diagnostic criteria; Rotterdam+NIH = all groups except self-reported; self-reported = 23andMe; and combined = all groups. Specific OR’s [95% CI, 5% CI] are indicated on the right. rs804279 in the GATA4/NEIL2 locus demonstrates significant heterogeneity (Het P = 2.6x10^-5). The * indicates statistically significant association for PCOS and the variant in that specific stratum.