Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis

Abstract

Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 × 10⁻⁷, odds ratio (OR) = 1.22, 95% CI 1.13-1.32) and for moderate to severe disease (P = 1.5 × 10⁻⁹, OR = 1.38, 95% CI 1.24-1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 × 10⁻³, OR = 1.17, 95% CI 1.06-1.28), resulting in a genome-wide significant P value of 1.4 × 10⁻⁹ (OR = 1.20, 95% CI 1.13-1.27) for 'all' endometriosis in our combined datasets of 5,586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.

Figure 1

Allele specific score prediction for (a) “all” endometriosis and (b) stage B endometriosis, using Oxford as the “discovery” and QIMR as the “target” dataset. Variance explained in the target dataset on the basis of allele specific scores derived in the discovery dataset for eight significance thresholds (P<0.01, P<0.05, P<0.1, P<0.2, P<0.3, P<0.4, P<0.5, P<0.75, plotted left to right in each study). The y-axis indicates Nagelkerke’s pseudo R² representing the proportion of variance explained. The number above each bar is the P value for the target dataset analysis. This figure shows that the results were not driven by a few highly associated regions, indicating a substantial number of common variants underlying disease.

Figure 2

Evidence for association with (a) “all” endometriosis and (b) stage B endometriosis across the chromosome 7 region following imputation using HapMap 3 and 1000 Genomes project CEU and TSI reference panels. SNP rs12700667 is represented by a purple diamond. All other SNPs are colour coded according to the strength of LD (as measured by r²) with rs12700667.