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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Scott, Robert A. ; Scott, Laura J ; Mägi, Reedik ; Marullo, Letizia ; Gaulton, Kyle J ; Kaakinen, Marika ; Almgren, Peter LU ; Lyssenko, Valeriya LU ; Groop, Leif LU and Franks, Paul LU (2017) In Diabetes 66(11). p.2888-2902
Abstract
To characterize 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 case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). 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... (More)
To characterize 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 case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). 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 single nucleotide variants. 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. © 2017 by the American Diabetes Association. (Less)
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author
; ; ; ; ; ; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Caucasian, gene expression regulation, genetic variation, genetics, genome-wide association study, human, non insulin dependent diabetes mellitus, physiology, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, ANDIS, diabetes, diabetics
in
Diabetes
volume
66
issue
11
pages
15 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:28566273
  • scopus:85030182446
ISSN
1939-327X
DOI
10.2337/db16-1253
language
English
LU publication?
yes
additional info
Cited By :4 Export Date: 25 January 2018
id
5867f78e-7daa-491d-a64c-af454921c7f1
date added to LUP
2018-01-25 13:11:25
date last changed
2024-05-14 00:07:53
@article{5867f78e-7daa-491d-a64c-af454921c7f1,
  abstract     = {{To characterize 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 case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P &lt;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 single nucleotide variants. 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. © 2017 by the American Diabetes Association.}},
  author       = {{Scott, Robert A. and Scott, Laura J and Mägi, Reedik and Marullo, Letizia and Gaulton, Kyle J and Kaakinen, Marika and Almgren, Peter and Lyssenko, Valeriya and Groop, Leif and Franks, Paul}},
  issn         = {{1939-327X}},
  keywords     = {{Caucasian; gene expression regulation; genetic variation; genetics; genome-wide association study; human; non insulin dependent diabetes mellitus; physiology; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Gene Expression Regulation; Genetic Variation; Genome-Wide Association Study; Humans; ANDIS; diabetes; diabetics}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2888--2902}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans}},
  url          = {{http://dx.doi.org/10.2337/db16-1253}},
  doi          = {{10.2337/db16-1253}},
  volume       = {{66}},
  year         = {{2017}},
}