Genome-Wide Association Study Identifies a Locus at 7p15.2 Associated With Endometriosis

Endometriosis affects 6% to 10% of women of reproductive age. Previous studies have demonstrated that risk of this disease is influenced by genetic factors; the estimated heritability is about 51%. Genome-wide association studies have investigated genetic variations in the DNA of women that predispose them to develop endometriosis, but have not addressed the genetic burden for different stages of disease severity. This genome-wide association study investigated the genetic loci associated with all endometriosis patients and with patients who had moderate to severe disease. The patient population comprised 3194 individuals with endometriosis (cases) and 7060 controls from Australia and the United Kingdom who were enrolled in the International Endogene Consortium study. The genetic loading of the different stages (all endometriosis cases and moderate to severe cases) was assessed. Analysis with polygenic predictive modeling showed that there was significantly increased genetic loading among 1364 cases with moderate to severe endometriosis. For both stages of endometriosis assessed, the strongest association was located at rs12700667 on chromosome 7p15.2. Cases with moderate to severe disease had a considerably stronger association with rs12700667 (P = 1.5 × 10−9; odds ratio [OR], 1.38; 95% confidence interval [CI], 1.24–1.53) compared with all endometriosis cases (P = 2.6 × 10−7; OR, 1.22; 95% CI, 1.13–1.32). Analysis of an independent cohort from the United States (2392 endometriosis cases and 2271 controls) replicated the association for all endometriosis cases with rs12700667 (P = 1.2 × 10−3; OR, 1.17; 95% CI, 1.06–1.28). Meta-analysis combining this dataset with the genome-wide association data (total of 5586 cases and 9331 controls) confirmed the association between all cases of endometriosis and rs12700667; the genome-wide significant P value was 1.4 × 10−9 with an OR of 1.20 (95% CI, 1.13–1.27). The rs12700667 site is located close to the presumptive candidate genes NFE2L3 and HOXA10, which are involved in placental and uterine development. These findings and the International Endogene Consortium data provide robust evidence that moderate to severe endometriosis is significantly more genetically driven than minimal to mild disease.