Rare mutations in WNT signaling pathways are risk factors for endometriosis

Abstract

Wnt proto-oncogenes are believed to play a role in endometriosis. Recently, genetic association studies have shown that common variants near Wnt4 are associated with endometriosis across different ethnicities. In order to test the hypothesis that variants in other genes involved in Wnt signaling pathways contribute to the pathogenesis of endometriosis, we tested exome variants found in 230 candidate genes involved in Wnt signaling for genetic association with endometriosis. A list of candidate genes involved in Wnt signaling were obtained using PANTHER database. 1537 Caucasian endometriosis patients were genotyped for 1138 rare exome variants in candidate genes. The number of heterozygous subjects observed was compared with published population data (n>50,000). 1537 patients with surgically confirmed endometriosis were tested using the Infinium HumanExome BeadChip (Illumina, San Diego, CA). Single marker association was tested using Fisher’s exact Test. In silico prediction of protein function was estimated using polyphen 2 database. We tested a total of 1138 variants representing 230 candidate Wnt genes. 88 showed causative/deleterious effect for endometriosis. After adjusting for multiple testing (p< 4.4E-05), we discovered 10 strongly associated variants in 10 distinct genes. None of these associated variants were predicted to be protein altering. The average OR among these associated variants is 10.7. Wnt signaling proteins, particularly the protocadherins, may play a major role in the pathogenesis of endometriosis.Table 1CHRPositionVar AlleleEndm FreqPopulation FreqGeneFisher pOR5140238124A0.06560.0131PCDHA107.54E-705.275140795212A0.00850.0005PCDHGA104.84E-2015.615140230533A0.00920.0020PCDHA91.94E-104.732246929692A0.06440.0399CELSR13.75E-101.651877170479A0.00390.0004NFATC12.62E-0810.735140250471A0.00200.0000PCDHA112.37E-0740.371710212619G0.00330.0004MYH131.83E-068.135140802374A0.00360.0006PCDHGA118.45E-065.911540581543G0.00490.0012PLCB21.74E-053.971668867265G0.00100.0000CDH12.41E-05Inf Open table in a new tab