Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

Abstract

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10^-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

Figure 1. Manhattan plot for genome-wide associations with endometriosis.

Data are based on GWA meta-analysis of all endometriosis cases. The horizontal axis shows the chromosomal position, and the vertical axis shows the significance of tested markers combined in a fixed-effects meta-analysis. Markers that reached genome-wide significance (P<5 × 10⁻⁸) are highlighted.

Figure 2. LocusZoom plots of five genome-wide significant endometriosis loci.

Association with endometriosis is expressed as −log₁₀(P value) for five new genome-wide significant loci: FN1 2q35 (2a), CCDC170 on 6q25.1 (2b), SYNE1 on 6q25.1 (2c), 7p12.3 (2d), and near FSHB on 11p14.1 (2e). Results for 2q35 and 7p12.3 are based on analysis including only moderate-to-severe ('Grade B') endometriosis cases. SNPs are shown as circles, diamonds or squares (filled or unfilled), with the top SNP represented by purple colour. All other SNPs are colour coded according to the strength of LD with the top SNP (as measured by r² in the European 1000 Genomes data).

Figure 3. Forest plots showing risk allele effects for five endometriosis loci.

Risk allele effects for the five new genome-wide significant loci in the individual case-control data sets and GWA meta-analysis: FN1 2q35 (3a), CCDC170 on 6q25.1 (3b), SYNE1 on 6q25.1 (3c), 7p12.3 (3d), and near FSHB on 11p14.1 (3e). Results for 2q35 and 7p12.3 are based on analysis including only moderate-to-severe ('Grade B') endometriosis cases. Risk allele effects of the remaining three SNPs are from analysis including all endometriosis cases.