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.
Highlights
Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; its molecular mechanisms remain largely unknown
Genome-wide association (GWA) studies have identified 11 independent single-nucleotide polymorphisms (SNPs) for endometriosis. These single nucleotide polymorphisms (SNPs) include rs10965235 in CDKN2BAS on chromosome 9p21.3 identified in a Japanese ancestry GWA study[5]; rs1519761 on 2q23.3 identified in a US GWA study of European-ancestry women[6]; seven loci (rs7521902 near WNT4 on 1p36.12, rs13391619 in GREB1 on 2p25.1, rs4141819 on 2p14, rs7739264 near ID4 on 6p22.3, rs12700667 on 7p15.2, rs1537377 near CDKN2B-AS1 on 9p21.3 and rs10859871 near VEZT on 12q22) identified in a Europeanancestry GWA study[7] and from a meta-analysis of European and Japanese ancestry GWA data[8]; and most recently rs17773813 near KDR on 4q12 and rs519664 in TTC39B on 9p22 in an Icelandic GWA study[9]
In addition to replicating 9 of the 11 previously reported European risk loci, this GWA meta-analysis identified 5 novel loci significantly associated with endometriosis risk (Po5 Â 10 À 8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB)
Summary
Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; its molecular mechanisms remain largely unknown. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (Po5 Â 10 À 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. In addition to replicating 9 of the 11 previously reported European risk loci, this GWA meta-analysis identified 5 novel loci significantly associated with endometriosis risk (Po5 Â 10 À 8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analyses identified five novel secondary association signals at these implicated loci, including two at the ESR1 locus, resulting in a total of 19 independent SNPs robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis
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