Genome-Wide Association Study Link Novel Loci to Endometriosis

Abstract

Endometriosis is a common gynecological condition with complex etiology defined by the presence of endometrial glands and stroma outside the womb. Endometriosis is a common cause of both cyclic and chronic pelvic pain, reduced fertility, and reduced quality-of-life. Diagnosis and treatment of endometriosis is, on average, delayed by 7–10 years from the onset of symptoms. Absence of a timely and non-invasive diagnostic tool is presently the greatest barrier to the identification and treatment of endometriosis. Twin and family studies have documented an increased relative risk in families. To identify genetic factors that contribute to endometriosis we conducted a two-stage genome-wide association study (GWAS) of a European cohort including 2,019 surgically confirmed endometriosis cases and 14,471 controls. Three of the SNPs we identify associated at P<5×10−8 in our combined analysis belong to two loci: LINC00339-WNT4 on 1p36.12 (rs2235529; P = 8.65×10−9, OR = 1.29, CI = 1.18–1.40) and RND3-RBM43 on 2q23.3 (rs1519761; P = 4.70×10−8, OR = 1.20, Cl = 1.13–1.29, and rs6757804; P = 4.05×10−8, OR = 1.20, Cl = 1.13–1.29). Using an adjusted Bonferoni significance threshold of 4.51×10−7 we identify two additional loci in our meta-analysis that associate with endometriosis:, RNF144B-ID4 on 6p22.3 (rs6907340; P = 2.19×10−7, OR = 1.20, Cl = 1.12–1.28), and HNRNPA3P1-LOC100130539 on 10q11.21 (rs10508881; P = 4.08×10−7, OR = 1.19, Cl = 1.11–1.27). Consistent with previously suggested associations to WNT4 our study implicate a 150 kb region around WNT4 that also include LINC00339 and CDC42. A univariate analysis of documented infertility, age at menarche, and family history did not show allelic association with these SNP markers. Clinical data from patients in our study reveal an average delay in diagnosis of 8.4 years and confirm a strong correlation between endometriosis severity and infertility (n = 1182, P<0.001, OR = 2.18). This GWAS of endometriosis was conducted with high diagnostic certainty in cases, and with stringent handling of population substructure. Our findings broaden the understanding of the genetic factors that play a role in endometriosis.

Independent Replication and Meta-Analysis for Endometriosis Risk Loci

“…The risk alleles and their frequencies for all the nine SNPs in the Belgian replication cohort were comparable with the original studies ( Table 2; Albertsen et al, 2013;Nyholt et al, 2012;Painter et al, 2011;Sapkota et al, 2015b). Moreover, direction of effects for seven of the nine SNPs for either 'All' or 'Grade_B' endometriosis was also consistent with the published results.…”

“…Our meta-analysis, including results from the current replication study and the published results, produced genome-wide significant evidence for six (rs7521902 near WNT4, rs13394619 in GREB1, rs6542095 in IL1A, rs7739264 near ID4, rs12700667 at 7p15.2, and rs1537377 near CDKN2B-AS1) of the nine implicated SNPs in either 'All' or 'Grade_B' endometriosis, after accounting for between-study heterogeneity using the RE2 model, wherever appropriate (Table 3). With the exception of rs1519761 at 2q23.3 reported by Albertsen et al (2013), the other two SNP loci (rs4141819 at 2p14 and rs10859871 near VEZT) also showed near genome-wide significance for 'Grade_B' endometriosis in the RE2 model (p = 3.63 × 10 −7 ) and for 'All' endometriosis in the fixed-effect model (p = 4.29 × 10 −7 ). The association signal for rs1519761 was the weakest ('All' , p = 5.62 × 10 −6 ; 'Grade_B' , p = 1.94 × 10 −6 ) among the nine risk loci, and the signal was slightly diluted after accounting for observed between-study heterogeneity in the RE2 model ('All' , p = 1.07 × 10 −5 ; 'Grade_B' , p = 7.99 × 10 −6 ).…”

Copy number variation analysis reveals additional variants contributing to endometriosis development

“…Our results are in agreement with previous studies that demonstrated an association between 1p36.33 and endometriosis [34][35][36]. This locus contains markers located in or near the WNT4 gene, which plays an important role on the development of the female reproductive tract and steroidogenesis [37,38].…”

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction

“…Gene symbols, expanded name and chromosome location are listed in Table 1 in alphabetical order for each of the 370 obesity genes. Similarly, 153 genes were found to be associated with human infertility and reproduction (Table 2) when searching the medical literature and based on genome-wide association, linkage and gene mutation or variant studies and 21 of these genes had a recognized role in obesity [32][33][34][35][36][37][38][39][40][41][42][43][44].…”