title: Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.
abstract: To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Momoko
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authors.lastname: Horikoshi
authors.affiliation: Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain, Josep Carreras Leukaemia Research Institute, Badalona, Spain, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Lorenzo
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authors.lastname: Pasquali
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Steven
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authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jeroen R
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authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Anubha
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authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
authors.forename: Jennifer L
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authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Teresa
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authors.lastname: Ferreira
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Adam E
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authors.lastname: Locke
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Neil R
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authors.affiliation: Saw Swee Hock School of Public Health.
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authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA, Saw Swee Hock School of Public Health.
authors.forename: Xueling
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authors.lastname: Sim
authors.affiliation: Department of Diabetes and Endocrinology, JR Tokyo General Hospital, Tokyo, Japan.
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authors.affiliation: Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
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authors.affiliation: Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, UK, Department of Epidemiology and Biostatistics.
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authors.forename: Sungkyoung
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authors.forename: Fumihiko
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authors.affiliation: Integrative Genomics and Modelization of Metabolic Diseases CNRS UMR8199, Lille Institute of Biology, E.G.I.D - FR3508 European Genomics Institute of Diabetes, Lille, France.
authors.forename: Dorothée
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authors.affiliation: Integrative Genomics and Modelization of Metabolic Diseases CNRS UMR8199, Lille Institute of Biology, E.G.I.D - FR3508 European Genomics Institute of Diabetes, Lille, France.
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authors.forename: Gonçalo
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA, Department of Genetics and Department of Medicine, Harvard Medical School, Boston, MA, USA, Department of Molecular Biology, Diabetes Research Center (Diabetes Unit), Department of Medicine.
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authors.forename: Ravindranath
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA, Diabetes Research Center (Diabetes Unit), Department of Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA, Center for Human Genetic Research, Department of Medicine, and.
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authors.affiliation: Department of Genomics of Common Disease, School of Public Health, Integrative Genomics and Modelization of Metabolic Diseases CNRS UMR8199, Lille Institute of Biology, E.G.I.D - FR3508 European Genomics Institute of Diabetes, Lille, France.
authors.forename: Philippe
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authors.forename: Taesung
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authors.initials: JS
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authors.forename: E Shyong
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authors.forename: Jorge
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authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK, Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK and.
authors.forename: Mark I
authors.initials: MI
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authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Department of Biostatistics, University of Liverpool, Liverpool, UK a.p.morris@liverpool.ac.uk.
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mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D044466:Asian People / Q000235:genetics; D002874:Chromosome Mapping; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D044465:White People / Q000235:genetics; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C498779:IGF2BP2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D016601:RNA-Binding Proteins; D012359:tRNA Methyltransferases; C525110:CDKAL1 protein, human