Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
Year: 2020
Type: article
Study design: Observational Study
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/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association 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 this T2D-risk allele 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.
Source: UNC Libraries
DOI: 10.17615/a6xp-1284
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: School of Medicine, Boston University, Hjerteforeningen, Universitetet i Tromsø, Foundation for Cardiovascular Research, Finska Läkaresällskapet, Wellcome Trust, Stiftelsen för Gamla Tjänarinnor, Tore Nilsons Stiftelse för Medicinsk Forskning, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Swedish e-Science Research Centre, National Institute for Health and Care Research, British Heart Foundation, Diabetes UK, European Commission, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Royal Swedish Academy of Sciences, Stiftelsen för Strategisk Forskning, Kela, Bundesministerium für Bildung und Forschung, Erasmus Medisch Centrum, Bundesministerium für Gesundheit, Hjärt-Lungfonden, Novo Nordisk, Signe ja Ane Gyllenbergin Säätiö, Etelä-Pohjanmaan Sairaanhoitopiiri, Stockholms Läns Landsting, Vetenskapsrådet, Danmarks Frie Forskningsfond, Augustinus Fonden, Norges Forskningsråd, Akademiska Sjukhuset, Sydäntutkimussäätiö, Uppsala Universitet, Svenska Läkaresällskapet, Diabetesliitto, Paavo Nurmen Säätiö, Pirkanmaan Sairaanhoitopiiri, Diabetestutkimussäätiö, Heinz Nixdorf Stiftung, European Regional Development Fund, NIHR Cambridge Biomedical Research Centre, Norwegian Institute of Public Health
Awards: G1044594144, Opening Estonian Genome Project for European Research Area, Sustainable and integrated production of liquid biofuels, bioenergy and green chemicals from glycerol in biorefineries, G1334132060, G1695511752, General and targeted approaches to unraveling the molecular causes of type 2 diabetes, ANDIS - All New Diabetics in Scania. A first step towards individualized medicine in diabetes care., Next-Generation Disease Association Analyses: Low pass Sequencing and High Density SNP genotyping for type 2 diabetes ., G2004031785, G2046098614, G2322197998, Characterising causal alleles for common disease., Bridging the gap from type 2 diabetes genetics to functional mechanisms of disease., G263730981, G292827090, G3227761751, G3805387446, G4037536873, G4280428318, Integriertes Forschungs- und Behandlungszentrum AdipositasErkrankungen, G459060772, European Network for Genetic and Genomic Epidemiology, G4733349049, G5571867242, G5612337485, G5713831584, G6079663390, G6154452564, G6644502431, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G729486055, G7318710736, G8170210843, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G890705022, Kompetenznetz Adipositas: zentrale Domäne 'Deutsche Adipositas Biomaterialbank', G894361248, The genetics of weight, BMI, adiposity and obesity, G927583753
OpenAlex ID: W4300821106