Format

Send to

Choose Destination
PLoS Genet. 2015 Jul 1;11(7):e1005230. doi: 10.1371/journal.pgen.1005230. eCollection 2015 Jul.

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
2
Estonian Genome Center, University of Tartu, Tartu, Estonia.
3
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
5
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
6
deCode Genetic - Amgen Inc, Reykjavik, Iceland.
7
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
8
Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
9
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
10
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
11
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
12
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
13
Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology and Center for Basic and Translational Obesity Research, Children's Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
14
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
15
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Cardiovascular Disease Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
16
Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany.
17
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
18
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
19
Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
20
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
21
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
22
Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.
23
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, United Kingdom.
24
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Steno Diabetes Center A/S, Gentofte, Denmark.
25
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Germany.
26
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
27
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
28
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Germany; Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
29
School of Population Health, University of South Australia, Adelaide, Australia; Centre for Paediatric Epidemiology and Biostatistics, University College London Institute of Child Health, London, United Kingdom.
30
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Center for Medical Systems Biology, Leiden, The Netherlands.
31
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
32
Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
33
Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland.
34
Bioinformatics and Biostatistics Support Hub (B/BASH), University of Leicester, Leicester, United Kingdom.
35
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK German Center for Cardiovascular Research, Partner Site Munich, Munich, Germany.
36
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland; The Department of Public Health, University of Helsinki, Helsinki, Finland.
37
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
38
Department of Medical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.
39
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
40
Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
41
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Folkhalsan Research Center, Helsinki, Finland; Vasa Central Hospital, Vasa, Finland; Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
42
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
43
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland.
44
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
45
Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.
46
Centre for Paediatric Epidemiology and Biostatistics, University College London Institute of Child Health, London, United Kingdom.
47
Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University & VU University Medical Center, Amsterdam, The Netherlands.
48
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
49
deCode Genetic - Amgen Inc, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
50
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland; The Department of Public Health, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
51
Deparment of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
52
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
53
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Estonian Genome Center, University of Tartu, Tartu, Estonia; Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

PMID:
26132169
PMCID:
PMC4488845
DOI:
10.1371/journal.pgen.1005230
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center