title: Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
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.
authors.affiliation: 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.
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authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Reedik
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authors.affiliation: 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.
authors.forename: Martijn
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authors.lastname: van de Bunt
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Ida
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authors.lastname: Surakka
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Antti-Pekka
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authors.lastname: Sarin
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
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authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
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authors.forename: Gudmar
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authors.affiliation: 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.
authors.forename: Sara
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authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jouke-Jan
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authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
authors.forename: Claes
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Janina S
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authors.affiliation: Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
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authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany.
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authors.affiliation: 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.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
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authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
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authors.affiliation: 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.
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authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.forename: Annette
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authors.affiliation: 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.
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authors.affiliation: 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.
authors.forename: Erik
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authors.lastname: Ingelsson
authors.affiliation: deCode Genetic - Amgen Inc, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
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authors.lastname: Thorsteinsdottir
authors.affiliation: deCode Genetic - Amgen Inc, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
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authors.lastname: Stefansson
authors.affiliation: 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.
authors.forename: Samuli
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authors.lastname: Ripatti
authors.affiliation: Deparment of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.affiliation: 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.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: 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.
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mesh_terms: D015992:Body Mass Index; D002874:Chromosome Mapping; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D000081410:Germinal Center Kinases; D005952:Glucose-6-Phosphatase / Q000235:genetics; D038321:Glycemic Index / Q000235:genetics*; D006801:Humans; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D019699:Thrombospondins / Q000235:genetics; D000098907:R-Spondins
chemical_list: D000081410:Germinal Center Kinases; D005952:Glucose-6-Phosphatase; D017346:Protein Serine-Threonine Kinases; D019699:Thrombospondins; C475438:RSPO3 protein, human; D000098907:R-Spondins; C492194:G6PC2 protein, human