The genetic architecture of type 2 diabetes · SciRah

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The genetic architecture of type 2 diabetes

Christian Fuchsberger^{a b c}, Jason A. Flannick^{d e}, Tanya M. Teslovich^b, Anubha Mahajan^{f g}, Vineeta Agarwala^{e h}, Kyle J. Gaulton^{f g}, Clement Ma^b, Pierre Fontanillas^e, Loukas Moutsianas^{f g}, Davis James McCarthy^{f g i}, Manuel A. Rivas^{f g}, John R. B. Perry

Nature Nature Portfolio2016-07-11 1,049 citations88 references

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Abstract

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

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^aCenter for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Bolzano, Italy
^bDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
^cDivision of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
^dDepartment of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
^eProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
^fWellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
^gNuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
^hHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
ⁱDepartment of Statistics, University of Oxford, Oxford, UK
^jDepartment of Twin Research and Genetic Epidemiology, King's College London, London, UK
^kGenetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK
^lMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
^mOxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
ⁿDepartment of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK
^oRadcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
^pMcGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada
^qSchool of Computer Science, McGill University, Montreal, Quebec, Canada
^rHuman Genetics Center, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas, USA
^sDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
^tNational Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA
^uMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
^vDepartment of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
^wChronic Disease Epidemiology, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland