1. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation
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Letizia Marullo, Jouke-Jan Hottenga, Kari Stefansson, Antti Jula, Johan Rung, Kyle J. Gaulton, Claes Ladenvall, Marian Beekman, Jeanine J. Houwing-Duistermaat, Anton J. M. de Craen, Nancy L. Pedersen, Teresa Ferreira, Jeanette Erdmann, Terho Lehtimӓki, Valgerdur Steinthorsdottir, Antti-Pekka Sarin, Christopher J. Groves, Anders Hamsten, Cecilia M. Lindgren, Veikko Salomaa, Unnur Thorsteinsdottir, Lennart C. Karssen, Valeriya Lyssenko, Cornelia M. van Duijn, Samuli Ripatti, Patrik K. E. Magnusson, Anubha Mahajan, Evelin Mihailov, Eco J. C. de Geus, P. Eline Slagboom, Martijn van de Bunt, Tõnu Esko, Andrew P. Morris, Aaron Isaacs, Sara Hӓgg, Jaakko Kaprio, Aki S. Havulinna, S Wiltshire, Sara M. Willems, Neil R. Robertson, Juan Fernandez, Momoko Horikoshi, Heribert Schunkert, Lars Lind, Erik Ingelsson, Yuri Milaneschi, Dorret I. Boomsma, Harald Grallert, Martina Müller-Nurasyid, Janina S. Ried, Gudmar Thorleifsson, Ida Surakka, Leif Groop, Joris Deelen, Martin D. Tobin, Jorma Viikari, Christian Gieger, Christian Herder, Natalia Pervjakova, Amanda J. Bennett, Matthew Blades, Annette Peters, Johannes H. Smit, Gonneke Willemsen, Markus Perola, Christina Willenborg, Thomas W. Winkler, Reedik Mӓgi, Iris M. Heid, Brenda W.J.H. Penninx, Michael Roden, Chris Power, Inga Prokopenko, Christopher P. Nelson, Elisabeth M. van Leeuwen, Mark I. McCarthy, Nilesh J. Samani, Johan G. Eriksson, Andres Metspalu, Olli T. Raitakari, Elina Hyppönen, Christian Hengstenberg, Gibson, Greg, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Institute for Molecular Medicine Finland, Clinicum, Jaakko Kaprio / Principal Investigator, Department of Public Health, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Leif Groop Research Group, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, Psychiatry, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, Epidemiology, General Practice, Dermatology, Immunology, Horikoshi, Momoko, Mägi, Reedik, van de Bunt, Martijn, Surakka, Ida, Hypponen, Elina, Morris, Andrew P, and ENGAGE Consortium
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Netherlands Twin Register (NTR) ,Cancer Research ,RARE GENETIC-VARIATION ,Obesity/genetics ,Genome-wide association study ,Body Mass Index ,Germinal Center Kinases ,0302 clinical medicine ,quantitative trait locus ,Gene Frequency ,genetic variability ,2.1 Biological and endogenous factors ,Aetiology ,Association mapping ,Genetics (clinical) ,2. Zero hunger ,Genetics ,G6PC2 gene ,Genetics & Heredity ,0303 health sciences ,INSULIN-RESISTANCE ,Glycemic Index/genetics ,Chromosome Mapping ,Single Nucleotide ,ENGAGE Consortium ,Protein-Serine-Threonine Kinases ,Polymorphism, Single Nucleotide/genetics ,ddc ,3. Good health ,fine-mapping ,Gene Frequency/genetics ,Glucose-6-Phosphatase ,LOW-FREQUENCY ,RSPO3 gene ,Life Sciences & Biomedicine ,Single Nucleotide/genetics ,Medical Genetics ,Research Article ,Biotechnology ,lcsh:QH426-470 ,Protein-Serine-Threonine Kinases/genetics ,Thrombospondins/genetics ,Quantitative Trait Loci ,Locus (genetics) ,Biology ,Endocrinology and Diabetes ,Protein Serine-Threonine Kinases ,GENOTYPE IMPUTATION ,Polymorphism, Single Nucleotide ,ASIAN POPULATIONS ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Humans ,Genetic Predisposition to Disease ,Obesity ,1000 Genomes Project ,GENOME-WIDE ASSOCIATION ,Polymorphism ,Molecular Biology ,Allele frequency ,Ecology, Evolution, Behavior and Systematics ,Metabolic and endocrine ,030304 developmental biology ,Genetic association ,Medicinsk genetik ,Nutrition ,Science & Technology ,Body mass index ,Molecular genetics ,Quantitative trait loci ,Genome-wide association studies ,Quality control ,Genomic signal processing ,Meta-analysis ,Human Genome ,gene mapping ,ta3121 ,Minor allele frequency ,BODY-MASS INDEX ,lcsh:Genetics ,Glucose-6-Phosphatase/genetics ,Glycemic Index ,glycemic control ,TYPE-2 DIABETES RISK ,3111 Biomedicine ,GCK gene ,WAIST-HIP RATIO ,Quantitative Trait Loci/genetics ,Thrombospondins ,030217 neurology & neurosurgery ,Imputation (genetics) ,FASTING GLUCOSE ,Genome-Wide Association Study ,Developmental Biology - 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., Author Summary Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
- Published
- 2015
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