Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Nat Genet
; 47(12): 1415-25, 2015 Dec.
Article
in En
| MEDLINE
| ID: mdl-26551672
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chromosome Mapping
/
Genetic Predisposition to Disease
/
Polymorphism, Single Nucleotide
/
Receptor, Melatonin, MT2
/
Diabetes Mellitus, Type 2
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Hepatocyte Nuclear Factor 3-beta
/
Genetic Loci
Type of study:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2015
Document type:
Article
Affiliation country:
Reino Unido
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA