TY - JOUR

T1 - Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry

AU - Sapkota, Yadav

AU - Vivo, Immaculata De

AU - Steinthorsdottir, Valgerdur

AU - Fassbender, Amelie

AU - Bowdler, Lisa

AU - Buring, Julie E.

AU - Edwards, Todd L.

AU - Jones, Sarah

AU - Dorien, O.

AU - Peterse, Daniëlle

AU - Rexrode, Kathryn M.

AU - Ridker, Paul M.

AU - Schork, Andrew J

AU - Thorleifsson, Gudmar

AU - Wallace, Leanne M.

AU - iPSYCH-SSI-Broad Group

AU - Kraft, Peter

AU - Morris, Andrew P.

AU - Nyholt, Dale R.

AU - Edwards, Digna R.Velez

AU - Nyegaard, Mette

AU - D'Hooghe, Thomas

AU - Chasman, Daniel I.

AU - Stefansson, Kari

AU - Missmer, Stacey A.

AU - Montgomery, Grant W.

AU - Werge, Thomas M.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-017-10440-9

DO - 10.1038/s41598-017-10440-9

M3 - Journal article

C2 - 28900119

AN - SCOPUS:85029324920

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 11380

ER -