An expanded genome-wide association study of Type 2 diabetes in Europeans
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Accepted version
Accepted version
Author(s)
Type
Journal Article
Abstract
To characterise type 2 diabetes (T2D) associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). We identified 13 novel T2D-associated loci (p<5×10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common SNVs. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion, and in adipocytes, monocytes and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Date Issued
2017-05-31
Date Acceptance
2017-05-21
Citation
Diabetes, 2017, 66 (11), pp.2888-2902
ISSN
0012-1797
Publisher
American Diabetes Association
Start Page
2888
End Page
2902
Journal / Book Title
Diabetes
Volume
66
Issue
11
Copyright Statement
© 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Sponsor
Commission of the European Communities
Wellcome Trust
Commission of the European Communities
Identifier
PII: db16-1253
Grant Number
633595
205915/Z/17/Z
626461
Subjects
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
GENETIC ARCHITECTURE
LOW-FREQUENCY
SUSCEPTIBILITY LOCI
FASTING GLUCOSE
RARE VARIANTS
RISK
RECEPTOR
PROVIDES
PATHOPHYSIOLOGY
METAANALYSIS
Diabetes Mellitus, Type 2
European Continental Ancestry Group
Gene Expression Regulation
Genetic Variation
Genome-Wide Association Study
Humans
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Humans
Diabetes Mellitus, Type 2
Gene Expression Regulation
European Continental Ancestry Group
Genetic Variation
Genome-Wide Association Study
Endocrinology & Metabolism
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2017-05-31