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

2.50
Hdl Handle:
http://hdl.handle.net/11287/618138
Title:
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
Authors:
Gaulton, K. J. [et al]; Frayling, Timothy M.; Hattersley, Andrew T.
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.
Citation:
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. 2015 Nature Genetics 47(12):1415-25
Publisher:
Nature
Journal:
Nature Genetics
Issue Date:
Dec-2015
URI:
http://hdl.handle.net/11287/618138
DOI:
10.1038/ng.3437
PubMed ID:
26551672
PubMed Central ID:
PMC4666734
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26551672/
Note:
This article is freely available via PubMed Central. Click on the 'Additional Link' above to access the full text.
Type:
Journal Article; Comparative Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language:
en
Appears in Collections:
2015 RD&E publications; Diabetes/Endocrine Services; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorGaulton, K. J. [et al]en
dc.contributor.authorFrayling, Timothy M.en
dc.contributor.authorHattersley, Andrew T.en
dc.date.accessioned2016-08-09T14:55:50Z-
dc.date.available2016-08-09T14:55:50Z-
dc.date.issued2015-12-
dc.identifier.citationGenetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. 2015 Nature Genetics 47(12):1415-25en
dc.identifier.pmid26551672-
dc.identifier.doi10.1038/ng.3437-
dc.identifier.urihttp://hdl.handle.net/11287/618138-
dc.description.abstractWe 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.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26551672/en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleGenetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility locien
dc.typeJournal Articleen
dc.typeComparative Studyen
dc.typeResearch Support, N.I.H., Extramuralen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalNature Geneticsen
dc.identifier.pmcidPMC4666734-
dc.description.noteThis article is freely available via PubMed Central. Click on the 'Additional Link' above to access the full text.en
dc.type.versionPublisheden

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