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Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease.

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Peters, James E 
Lyons, Paul A 
Lee, James C 
Richard, Arianne C 
Fortune, Mary D 

Abstract

Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46) and healthy controls (n = 43), revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases.

Description

Keywords

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Female, Gene Expression Regulation, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Male, Monocytes, Neutrophils, Phenotype, Quantitative Trait Loci, T-Lymphocytes

Journal Title

PLoS Genetics

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

12

Publisher

Public Library of Science (PLoS)
Sponsorship
Wellcome Trust (083650/Z/07/Z)
Medical Research Council (MR/L019027/1)
Medical Research Council (G0400929)
ARTHRITIS RESEARCH UK (20593)
We thank the patients who kindly volunteered for this study. We thank Miles Parkes 873 and the staff from the Inflammatory Bowel Disease clinic and David Jayne and the staff 874 of the Vasculitis and Lupus clinic at Addenbrooke’s Hospital for helping to identify and 875 recruit suitable patients. AAV patients were genotyped through the European Vasculitis 876 Genetics Consortium. Pablo Moreno provided assistance with use of the CIMR 877 computing cluster. James Wason provided statistical advice. We thank Arthur Kaser 878 and John Todd for their review of the manuscript.