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

Sapkota, Yadav, De Vivo, Immaculata, Steinthorsdottir, Valgerdur, Fassbender, Amelie, Bowdler, Lisa, Buring, Julie E., Edwards, Todd L., Jones, Sarah, Dorien, O., Peterse, Danielle, Rexrode, Kathryn M., Ridker, Paul M., Schork, Andrew J., Thorleifsson, Gudmar, Wallace, Leanne M., Kraft, Peter, Morris, Andrew P., Nyholt, Dale R., Edwards, Digna R. Velez, Nyegaard, Mette, D'Hooghe, Thomas, Chasman, Daniel I., Stefansson, Kari, Missmer, Stacey A. and Montgomery, Grant W. (2017) Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry. Scientific Reports, 7 1: 11380. doi:10.1038/s41598-017-10440-9

Author Sapkota, Yadav
De Vivo, Immaculata
Steinthorsdottir, Valgerdur
Fassbender, Amelie
Bowdler, Lisa
Buring, Julie E.
Edwards, Todd L.
Jones, Sarah
Dorien, O.
Peterse, Danielle
Rexrode, Kathryn M.
Ridker, Paul M.
Schork, Andrew J.
Thorleifsson, Gudmar
Wallace, Leanne M.
Kraft, Peter
Morris, Andrew P.
Nyholt, Dale R.
Edwards, Digna R. Velez
Nyegaard, Mette
D'Hooghe, Thomas
Chasman, Daniel I.
Stefansson, Kari
Missmer, Stacey A.
Montgomery, Grant W.
Title Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2017-09-01
Sub-type Article (original research)
DOI 10.1038/s41598-017-10440-9
Open Access Status DOI
Volume 7
Issue 1
Start page 11380
Total pages 11
Language eng
Subject 1000 General
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) 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.
Keyword Genome-Wide Association
Rare Variants
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 HL043851
UM1 CA176726
UM1 CA182913
R01 CA047988
R01 HL080467
R01 HD057210
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
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