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Genome-wide association studies (GWAS) have identified markers within the  WNT4  region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk ( P  =   1.84 × 10 −5 , OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of  LINC00339  (also known as  HSPC157 ) and increasing expression of  CDC42  ( P  =   2.0 ×10 −54  and 4.5x10 −4  respectively). The largest effects were for two  LINC00339  probes ( P  =   2.0 ×10 −54 ; 1.0 × 10 −34 ). The eQTL for  LINC00339  was also observed in endometrial tissue ( P  =   2.4 ×10 −8 ) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for  WNT4 . Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both  LINC00339  and  CDC4  and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for  CDC42  and the risk allele increases expression of  CDC42.  However, no effect of rs3820282 was observed in the  LINC00339  expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both  LINC00339  and  CDC42 .

Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339