Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets

Abstract

Background: Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition.

Methods: Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations.

Results: Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10(-8)), including rs12700667 on 7p15.2 (P = 1.6 × 10(-9)), rs7521902 near WNT4 (P = 1.8 × 10(-15)), rs10859871 near VEZT (P = 4.7 × 10(-15)), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10(-8)), rs7739264 near ID4 (P = 6.2 × 10(-10)) and rs13394619 in GREB1 (P = 4.5 × 10(-8)). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10(-8)) and rs4141819 on 2p14 (P = 9.2 × 10(-8)). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis.

Conclusions: Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways.

Keywords: GWAS; endometriosis; genetics; heterogeneity; sub-phenotypes.

Figure 1

Schematic overview of all genome-wide associations (P ≤ 5 × 10⁻⁸) across all chromosomes (small window) and endometriosis associations (large window), presented in 17 trait categories (colour coded), generated from the NHGRI GWA Catalog (Hindorff et al., 2009). Available at: www.genome.gov/gwastudies (accessed 11 October 2013).

Figure 2

Forest plots showing the effects of risk alleles for SNPs in six loci reaching genome-wide significance for association with all endometriosis and two loci reaching borderline genome-wide significance with only Stage III/IV cases in the meta-analysis. BBJ_Rep, BioBank Japan replication.

Figure 3

Linkage disequilibrium structure for the region containing rs1537377, rs1333049 and rs10965235 in/near CDKN2BAS on chromosome 9 in individuals of European ancestry (bottom panel) and of Japanese ancestry (top panel) (Source: http://hapmap.ncbi.nlm.nih.gov).

Figure 4

Diagrams showing the 9 genes closest to each of the 11 endometriosis SNPs included in the meta-analysis. Exons (coding regions) are presented with grey coloured boxes; lines between the exons present introns (non-coding genic regions); empty white boxes at the ends of the genes represent the 3′ and 5′ UTR regions. Each endometriosis SNP is illustrated in red, along with its distance to the gene where relevant (red arrows). SNPs genome wide associated with other trait/disease associations, that are in linkage disequilibrium (r² > 0.2) with any of the endometriosis SNPs are illustrated in blue. See Supplementary data, Table SI for a complete list of all published SNP associations for these genomic regions including independent signals.