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

Sci Rep. 2017 Sep 12;7(1):11380. doi: 10.1038/s41598-017-10440-9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Case-Control Studies
  • Chromosome Mapping
  • Endometriosis / genetics*
  • Endometriosis / metabolism*
  • European Continental Ancestry Group*
  • Exome
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study*
  • Humans
  • Meta-Analysis as Topic
  • Polymorphism, Single Nucleotide
  • Whole Exome Sequencing

Substances

  • Biomarkers