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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.

Original publication

DOI

10.1038/ng.3437

Type

Journal article

Journal

Nature genetics

Publication Date

12/2015

Volume

47

Pages

1415 - 1425

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Keywords

DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Liver, Islets of Langerhans, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Receptor, Melatonin, MT2, Case-Control Studies, Chromatin Immunoprecipitation, Chromosome Mapping, Genomics, Gene Expression Regulation, Binding Sites, Polymorphism, Single Nucleotide, Hepatocyte Nuclear Factor 3-beta, Genome-Wide Association Study, Genetic Loci, Molecular Sequence Annotation