Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
2015 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, 1415- p.Article in journal (Refereed) PublishedText
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.
Place, publisher, year, edition, pages
2015. Vol. 47, no 12, 1415- p.
IdentifiersURN: urn:nbn:se:uu:diva-272135DOI: 10.1038/ng.3437ISI: 000365813200013PubMedID: 26551672OAI: oai:DiVA.org:uu-272135DiVA: diva2:893154
FunderGerman Research Foundation (DFG), ER 155/6-2EU, European Research Council, ENGAGE HEALTH-F4-2007-201413EU, FP7, Seventh Framework Programme, FP7-201413EU, FP7, Seventh Framework Programme, FP7-245536EU, European Research Council, EXGENESIS LSHM-CT-2004-005272EU, European Research Council, FP6 LSHM_CT_2006_037197EU, European Research Council, LSHM-CT-2007-037273EU, European Research Council, C-Public Health 2004310Stiftelsen Gamla TjänarinnorThe Karolinska Institutet's Research FoundationKnut and Alice Wallenberg Foundation, KAW 2009.0243Magnus Bergvall FoundationNIH (National Institute of Health), HHSN268200625226CNIH (National Institute of Health), UL1RR025005NIH (National Institute of Health), R01DK062370NIH (National Institute of Health), R01DK072193NIH (National Institute of Health), 1Z01HG000024NIH (National Institute of Health), AG028555NIH (National Institute of Health), AG08724NIH (National Institute of Health), AG04563NIH (National Institute of Health), AG10175NIH (National Institute of Health), AG08861NIH (National Institute of Health), U01HG004399NIH (National Institute of Health), DK58845NIH (National Institute of Health), CA055075NIH (National Institute of Health), DK085545NIH (National Institute of Health), DK098032Novo NordiskSwedish Diabetes AssociationSwedish Foundation for Strategic Research Swedish Heart Lung FoundationSwedish Research Council, SFO EXODIAB 2009-1039Swedish Research Council, 521-2010-3490Swedish Research Council, 521-2007-4037Swedish Research Council, 521-2008-2974Swedish Research Council, ANDIS 825-2010-5983Swedish Research Council, LUDC 349-2008-6589Swedish Research Council, 8691Swedish Society of MedicineTorsten Söderbergs stiftelseWellcome trust, GR072960Wellcome trust, 076113Wellcome trust, 083948Wellcome trust, 090367Wellcome trust, 090532Wellcome trust, 083270Wellcome trust, 086596Wellcome trust, 098017Wellcome trust, 095101Wellcome trust, 098051Wellcome trust, 098381