Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry

Yadav Sapkota, Immaculata De Vivo, Valgerdur Steinthorsdottir, Amelie Fassbender, Lisa Bowdler, Julie E. Buring, Todd L. Edwards, Sarah Jones, Dorien O, Daniëlle Peterse, Kathryn M. Rexrode, Paul M. Ridker, Andrew J. Schork, Gudmar Thorleifsson, Leanne M. Wallace, iPSYCH-SSI-Broad Group, Peter Kraft, Andrew P. Morris, Dale R. Nyholt, Digna R. Velez Edwards, Mette Nyegaard, Thomas D’Hooghe, Daniel I. Chasman, Kari Stefansson, Stacey A. Missmer, Grant W. Montgomery

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10(-9)) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.