Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Autor: Mahajan A; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Sim X; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Ng HJ; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Manning A; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Rivas MA; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Highland HM; Human Genetics Center, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America., Locke AE; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Grarup N; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Im HK; Department of Health Studies, Biostatistics Laboratory, The University of Chicago, Chicago, Illinois, United States of America., Cingolani P; School of Computer Science, McGill University, Montreal, Quebec, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada., Flannick J; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America., Fontanillas P; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Fuchsberger C; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Gaulton KJ; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Teslovich TM; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Rayner NW; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom., Robertson NR; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Beer NL; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Rundle JK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Bork-Jensen J; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ladenvall C; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden., Blancher C; High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Buck D; High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Buck G; High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Burtt NP; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Gabriel S; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Gjesing AP; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Groves CJ; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Hollensted M; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Huyghe JR; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Jackson AU; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Jun G; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Justesen JM; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Mangino M; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom., Murphy J; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Neville M; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Onofrio R; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Small KS; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom., Stringham HM; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Syvänen AC; Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Trakalo J; High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Abecasis G; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Bell GI; Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America., Blangero J; Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America., Cox NJ; Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois, United States of America., Duggirala R; Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America., Hanis CL; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America., Seielstad M; Blood Systems Research Institute, San Francisco, California, United States of America; Department of Laboratory Medicine & Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States of America., Wilson JG; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America., Christensen C; Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark., Brandslund I; Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark., Rauramaa R; Foundation for Research in Health, Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland., Surdulescu GL; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom., Doney AS; Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom., Lannfelt L; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden., Linneberg A; Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark., Isomaa B; Department of Social Services and Health Care, Jakobstad, Finland; Folkhälsan Research Centre, Helsinki, Finland., Tuomi T; Folkhälsan Research Centre, Helsinki, Finland; Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland., Jørgensen ME; Steno Diabetes Center, Gentofte, Denmark., Jørgensen T; Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; Faculty of Medicine, University of Aalborg, Aalborg, Denmark., Kuusisto J; Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Kuopio University Hospital, Kuopio, Finland., Uusitupa M; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland., Salomaa V; National Institute for Health and Welfare, Helsinki, Finland., Spector TD; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom., Morris AD; Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom., Palmer CN; Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom., Collins FS; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America., Mohlke KL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America., Bergman RN; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California, United States of America., Ingelsson E; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Lind L; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Tuomilehto J; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia; Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), University Hospital LaPaz, Autonomous University of Madrid, Madrid, Spain; Center for Vascular Prevention, Danube University Krems, Krems, Austria; Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland., Hansen T; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark., Watanabe RM; Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America; Diabetes and Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America., Prokopenko I; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom., Dupuis J; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America., Karpe F; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom., Groop L; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden., Laakso M; Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Kuopio University Hospital, Kuopio, Finland., Pedersen O; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Florez JC; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America., Morris AP; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Estonian Genome Centre, University of Tartu, Tartu, Estonia., Altshuler D; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America., Meigs JB; General Medicine Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., Boehnke M; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., McCarthy MI; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom., Lindgren CM; Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America., Gloyn AL; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2015 Jan 27; Vol. 11 (1), pp. e1004876. Date of Electronic Publication: 2015 Jan 27 (Print Publication: 2015).
DOI: 10.1371/journal.pgen.1004876
Abstrakt: Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
Databáze: MEDLINE