Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Nat Genet
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
12
Pages
1415-25
Date Published
2015 Dec
ISSN
1546-1718
URL
DOI
10.1038/ng.3437
PubMed ID
26551672
PubMed Central ID
PMC4666734
Links
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R01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
AG04563 / AG / NIA NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
R01 DK073490 / DK / NIDDK NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
G0000649 / Medical Research Council / United Kingdom
098017 / Wellcome Trust / United Kingdom
British Heart Foundation / United Kingdom
R01 DK058845 / DK / NIDDK NIH HHS / United States
RG/08/008/25291 / British Heart Foundation / United Kingdom
N01HG65403 / HG / NHGRI NIH HHS / United States
K24DK080140 / DK / NIDDK NIH HHS / United States
GR072960 / Wellcome Trust / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01 HG065403 / HG / NHGRI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
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086596 / Wellcome Trust / United Kingdom
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PG/11/4/28645 / British Heart Foundation / United Kingdom
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101033 / Wellcome Trust / United Kingdom
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MC_U106179471 / Medical Research Council / United Kingdom
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090367 / Wellcome Trust / United Kingdom
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098051 / Wellcome Trust / United Kingdom
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U01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100007C / PHS HHS / United States
098395 / Wellcome Trust / United Kingdom
AG08724 / AG / NIA NIH HHS / United States
DK098032 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01DK072193 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
RG/14/5/30893 / British Heart Foundation / United Kingdom
G116/165 / Medical Research Council / United Kingdom
CA055075 / CA / NCI NIH HHS / United States
Z01 HG000024 / HG / NHGRI NIH HHS / United States
095101 / Wellcome Trust / United Kingdom
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098381 / Wellcome Trust / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States
G0601261 / Medical Research Council / United Kingdom
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