Genome-wide association meta-analysis identifies new endometriosis risk loci

Abstract

We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10(-3)), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10(-8) in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10(-11)), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.

Figure 1

Study design.

Figure 2

Evidence for association with endometriosis from the QIMRHCS+OX+BBJ GWA meta-analysis across the 1p36.12 (a), 6p22.3 (b), 9p21.3 (c) and 12q22 (d) regions following imputation using the 1000 Genomes Project reference panel. Diamond and circle symbols represent genotyped and imputed SNPs, respectively. The most significant genotyped SNP is represented by a purple diamond. All other SNPs are color coded according to the strength of LD with the top genotyped SNP (as measured by r² in the European 1000 Genomes data).

Figure 3

Forest plots of risk allele effects for the seven genome-wide significant SNP loci in the individual and total endometriosis case-control cohorts.

Figure 4

Allele-specific score prediction for endometriosis, using the BBJ population as the discovery dataset and the QIMRHCS+OX population as the target dataset. The variance explained in the target dataset on the basis of allele-specific scores derived in the discovery dataset for twelve significance thresholds (P < 0.01, P < 0.05, P < 0.1, P < 0.2, P < 0.3, P < 0.4, P < 0.5, P < 0.6, P < 0.7, P < 0.8, P < 0.9, P < 1.0, plotted left to right). 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 prediction analysis (i.e. R² significance). Prediction was performed using all GWA meta-analysis SNPs (a) and after excluding all SNPs within ±2500 kb of the seven implicated SNPs listed in Table 1 (b). These figures show that the results were not driven by a few highly associated regions, indicating a substantial number of common variants underlie endometriosis risk.