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PLoS Genet. 2015 Jan 27;11(1):e1004876. doi: 10.1371/journal.pgen.1004876. eCollection 2015 Jan.

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

Author information

1
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
3
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
4
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
5
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.
6
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
7
Department of Health Studies, Biostatistics Laboratory, The University of Chicago, Chicago, Illinois, United States of America.
8
School of Computer Science, McGill University, Montreal, Quebec, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
9
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.
10
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.
11
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.
12
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
13
High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
15
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
16
Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
17
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
18
Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois, United States of America.
19
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
20
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.
21
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
22
Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
23
Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
24
Foundation for Research in Health, Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
25
Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom.
26
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
27
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.
28
Department of Social Services and Health Care, Jakobstad, Finland; Folkhälsan Research Centre, Helsinki, Finland.
29
Folkhälsan Research Centre, Helsinki, Finland; Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
30
Steno Diabetes Center, Gentofte, Denmark.
31
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
32
Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Kuopio University Hospital, Kuopio, Finland.
33
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
34
National Institute for Health and Welfare, Helsinki, Finland.
35
Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom.
36
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom.
37
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
38
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
39
Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California, United States of America.
40
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.
41
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
42
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.
43
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.
44
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.
45
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.
46
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.
47
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.
48
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.
49
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.
50
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.
51
General Medicine Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
52
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.
53
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.

Abstract

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.

PMID:
25625282
PMCID:
PMC4307976
DOI:
10.1371/journal.pgen.1004876
[Indexed for MEDLINE]
Free PMC Article

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