Mutations in the GnRH signaling pathway are risk factors for endometriosis

Abstract

Some but not all patients with endometriosis have abnormal functioning of their GnRH axis and some but not all endometriosis patients respond to GnRH agonist therapies. The clinical variation observed may be caused by instrinsic genetic variation in these pathways. We tested 177 genes involved in human GnRH signaling for genetic association with endometriosis. Candidate genes involved in human GnRH signaling pathways were obtained using PANTHER database. 1537 Caucasian endometriosis patients were genotyped for 570 exome variants in 179 candidate genes. The frequency of heterozygous affected women was compared with published population data (n>50,000 population controls). Human Exome Beadchips (Illumina, San Diego, CA) were used for genotyping. Single marker association was tested using Fisher’s Exact Test. In silico prediction of protein function was evaluated using the Polyphen 2 database. We tested 570 exome variants representing 177 genes involved in GnRh signaling pathway that showed a causative/deleterious effect. After adjusting for multiple testing (p<8.7E-05), we discovered 5 exome variants representing 5 different genes as shown in Table 1. The top 2 significantly associated variants (CRTC1 and ARHGAP32) are predicted to be damaging to the encoded protein.Table 1CHRPositionVar AlleleEndm FreqPopulation FreqGeneFisher pOR1918876309G0.160990.08759CRTC19.51E-372.0011128839405A0.042070.02420ARHGAP328.09E-091.771877170479A0.003900.00037NFATC12.62E-0810.73112161530A0.001950.000048IGF22.37E-0740.37636075326A0.001300.000029MAPK142.28E-0544.83 Open table in a new tab Gene variants affecting the human GnRH signaling pathway are significant risk factors for predisposition to endometriosis. These gene variants are likely to contribute to the clinical variation observed in women with endometriosis.