Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Author(s)
Type
Journal Article
Abstract
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Date Issued
2015-11-09
Date Acceptance
2015-10-07
Citation
Nature Genetics, 2015, 47 (12), pp.1415-1425
ISSN
1546-1718
Publisher
Nature Publishing Group
Start Page
1415
End Page
1425
Journal / Book Title
Nature Genetics
Volume
47
Issue
12
Copyright Statement
© 2015 Nature America, Inc. All rights reserved
Sponsor
Wellcome Trust
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Grant Number
101033/C/13/Z
RDC03 79560
RDC03 79560
MR/L02036X/1
MR/L02036X/1
RDB03 79560
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
LARGE-SCALE ASSOCIATION
HUMAN PANCREATIC-ISLETS
WIDE ASSOCIATION
BETA-CELL
TRANSCRIPTION FACTORS
GLUCOSE-HOMEOSTASIS
GENOTYPE IMPUTATION
INSULIN-SECRETION
COMMON VARIANTS
GLYCEMIC TRAITS
Publication Status
Published