Replication of endometriosis GWAS signal across multiple studies support involvement of WNT4

Abstract

Recent genome-wide association studies (GWAS) searching for genes associated with endometriosis have had limited power. Assuming that genetic risks underlying endometriosis are comparable to other complex diseases, we expect that many true endometriosis associations are present in the data with P-values below genome wide significance. To investigate this we compared association and trends for several single nucleotide polymorphisms (SNPs) in this range from published studies with SNPs identified in our investigations. SNPs reported by Uno et al. (2010) and Painter et al. (2011) as being moderately associated with endometriosis are compared to SNPs identified in our GWAS. Two large GWAS have been completed in our laboratory using two genotyping platforms. Genetic analysis was performed using PLINK ver 1.07. Findings from our GWAS identify rs2235529 (P-value=3.7e-05) and rs4654783 (P-value=6.1e-05) to be associated with endometriosis in a Caucasian population, and support the involvement of WNT4 previously reported. Further, of 173 SNPs reported in the supplementary tables 104 were genotyped in our studies. Twenty-two of the 104 SNPs had allelic P-values <0.05 in our studies. The risk and odds-ratio-trend were concordant for 17 of the 22 snps when compared with the published results. Four SNPs with discordant trends were observed comparing distinct ethnic populations (Caucasian vs. Japanese), while a single SNP showed discordance in Caucasians. We observe a general concordance between risk-alleles and odds-ratio-trends of moderately associated SNPs in separate GWAS studies. We expect that many additional SNPs, truly associated with endometriosis, can be identified in appropriately powered GWAS. Our data suggest that SNPs (and pathways) that regulate the development of endometriosis are similar across ethnic groups. Comparison of weakly associated SNPs between separate GWAS studies is encouraged to identify SNPs that ordinarily would be disregarded.