An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
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Abstract
To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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The record
- Venue
- Diabetes
- Topic
- Genetic Associations and Epidemiology
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- —
- Funders
- National Institute on AgingNational Institutes of HealthH. Lundbeck A/SNovo Nordisk Foundation Center for Basic Metabolic ResearchUniversität UlmNational Center for Research ResourcesDiabetesliittoRheinische Friedrich-Wilhelms-Universität BonnSvenska KulturfondenCopenhagen Graduate School for Nanoscience and NanotechnologySydäntutkimussäätiöMedizinischen Hochschule HannoverBroad InstituteNIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchFondation de FranceHorizon 2020 Framework ProgrammeVetenskapsrådetGlaxoSmithKlineSigne ja Ane Gyllenbergin SäätiöGenome CanadaNovo NordiskAlfred Benzon FoundationKuopion Yliopistollinen SairaalaKarolinska InstitutetUniversity of ExeterDeutsche ForschungsgemeinschaftNederlandse Organisatie voor Wetenschappelijk OnderzoekSamfundet FolkhälsanPäivikki ja Sakari Sohlbergin SäätiöEuropean Regional Development FundTerveyden ja hyvinvoinnin laitosAcademy of FinlandEesti TeadusagentuurKelaMinerva FoundationInstitut National de la Santé et de la Recherche MédicaleEuropean Foundation for the Study of DiabetesUniversity of OxfordQueen Mary University of LondonFolkhälsanin TutkimussäätiöNational Institute for Health and Care ResearchCentre of Excellence for Environmental Decisions, Australian Research CouncilLee Kong Chian School of Medicine, Nanyang Technological UniversityJohns Hopkins UniversityNational Heart, Lung, and Blood InstituteNanyang Technological UniversityNovo Nordisk FondenUniversità degli Studi di FerraraAmerican Heart AssociationErasmus Universitair Medisch Centrum RotterdamEuropean CommissionMassachusetts Institute of TechnologySchool of Medicine, Boston UniversityHelsingin YliopistoSteno Diabetes Center CopenhagenNational Cancer InstituteLundbeckfondenUniversity College LondonWellcome TrustPfizerMedical Research CouncilIncyteFoundation for Cardiovascular ResearchBritish Heart FoundationBrigham and Women's HospitalAmgenNational Institute of Diabetes and Digestive and Kidney DiseasesHelsingin ja Uudenmaan SairaanhoitopiiriImperial College LondonNational Human Genome Research InstituteDanmarks Frie ForskningsfondAndrea and Charles Bronfman Philanthropies
- Keywords
- Genome-wide association studyImputation (statistics)BiologyGenetic associationType 2 diabetesSingle-nucleotide polymorphismGeneticsHaplotype1000 Genomes ProjectPopulation stratificationQuantitative trait locusLocus (genetics)Allele frequencyAlleleExpression quantitative trait lociComputational biologyGeneDiabetes mellitusGenotypeEndocrinologyMissing data
- Has abstract in OpenAlex
- yes