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

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

Author information

1
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Yadav.Sapkota@stjude.org.
2
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA. Yadav.Sapkota@stjude.org.
3
Harvard Medical School, Boston, MA, USA.
4
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
5
deCODE genetics/Amgen, Reykjavik, Iceland.
6
KULeuven, Department of Development and Regeneration, Organ systems, Leuven, Belgium.
7
Department of Obstetrics and Gynaecology, Leuven University Fertility Centre, University Hospital Leuven, Leuven, Belgium.
8
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
9
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
10
Institute of Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA.
11
Vanderbilt Genetics Institute, Division of Epidemiology, Institute of Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
12
Cognitive Science Department, University of California, San Diego, La Jolla, California, USA.
13
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, DK-2100, Copenhagen, Denmark.
14
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
15
Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
16
Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia.
17
Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute of Medicine and Public Health, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
18
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
19
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
20
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
21
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

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.

PMID:
28900119
PMCID:
PMC5595920
DOI:
10.1038/s41598-017-10440-9
[Indexed for MEDLINE]
Free PMC Article

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