Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Research output: Contribution to journalArticlepeer-review

Authors

  • EPIC-InterAct Consortium
  • Jennifer Wessel
  • Audrey Y Chu
  • Sara M Willems
  • Shuai Wang
  • Hanieh Yaghootkar
  • Jennifer A Brody
  • Marco Dauriz
  • Marie-France Hivert
  • Sridharan Raghavan
  • Leonard Lipovich
  • Bertha Hidalgo
  • Keolu Fox
  • Jennifer E Huffman
  • Ping An
  • Yingchang Lu
  • Laura J Rasmussen-Torvik
  • Niels Grarup
  • Margaret G Ehm
  • Li Li
  • Abigail S Baldridge
  • Alena Stančáková
  • Ravinder Abrol
  • Céline Besse
  • Anne Boland
  • Jette Bork-Jensen
  • Myriam Fornage
  • Daniel F Freitag
  • Melissa E Garcia
  • Xiuqing Guo
  • Kazuo Hara
  • Aaron Isaacs
  • Johanna Jakobsdottir
  • Leslie A Lange
  • Jill C Layton
  • Man Li
  • Jing Hua Zhao
  • Karina Meidtner
  • Alanna C Morrison
  • Mike A Nalls
  • Marjolein J Peters
  • Maria Sabater-Lleal
  • Claudia Schurmann
  • Angela Silveira
  • Albert V Smith
  • Lorraine Southam
  • Marcus H Stoiber
  • Rona J Strawbridge
  • Kent D Taylor
  • Tibor V Varga
  • Kristine H Allin
  • James Brown

Colleges, School and Institutes

External organisations

  • 1] Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
  • 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
  • 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0SL, UK.
  • Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  • University of Exeter
  • 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
  • 1] Massachusetts General Hospital, General Medicine Division, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona 37126, Italy.
  • 1] Harvard Pilgrim Health Care Institute, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Division of Endocrinology and Metabolism, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1K 2R1 [3] Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • 1] Massachusetts General Hospital, General Medicine Division, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 1] Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA [2] Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48202, USA.
  • Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
  • 1] Department of Medicine, University of Washington, Seattle, Washington 98195, USA [2] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
  • 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland EH4 2XU, UK.
  • Division of Statistical Genomics and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
  • 1] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
  • The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
  • Quantitative Sciences, PCPS, GlaxoSmithKline, North Carolina 27709, USA.
  • Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio FI-70211, Finland.
  • 1] Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA.
  • CEA, Institut de Génomique, Centre National de Génotypage, 2 Rue Gaston Crémieux, EVRY Cedex 91057, France.
  • Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA.
  • University of Cambridge
  • Intramural Research Program, National Institute on Aging, Bethesda, Maryland 21224, USA.
  • Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
  • Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
  • Icelandic Heart Association, Holtasmari 1, Kopavogur IS-201, Iceland.
  • Systems Genetics Core Facility, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
  • Indiana University, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA.
  • Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
  • Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal DE-14558, Germany.
  • Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77225, USA.
  • Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA.
  • 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam 2300 RC, The Netherlands.
  • Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden.
  • 1] Icelandic Heart Association, Holtasmari 1, Kopavogur IS-201, Iceland [2] University of Iceland, Reykjavik IS-101, Iceland.
  • 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
  • Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;
  • Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital, Malmö SE-205 02, Sweden.

Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l-1, P=3.4 × 10-12), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10-6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l-1, P=1.3 × 10-8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Details

Original languageEnglish
Article number5897
Number of pages16
JournalNature Communications
Volume6
Publication statusPublished - 29 Jan 2015

Keywords

  • African Continental Ancestry Group/genetics, Blood Glucose/metabolism, Diabetes Mellitus, Type 2/blood, European Continental Ancestry Group/genetics, Exome/genetics, Fasting/blood, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor/genetics, Glucose-6-Phosphatase/genetics, Humans, Insulin/blood, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics