Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
Year: 2012
Type: article
Study design: Observational Study
Abstract: AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Source: Diabetologia
Authors: D.E.S.I.R. Study Group, A. Albrechtsen, N. Grarup, Y. Li, T. Sparsø, G. Tian, H. Cao, T. Jiang, S. Y. Kim, T. Korneliussen, Q. Li, C. Nie, R. Wu, L. Skotte, A. P. Morris, C. Ladenvall, S. Cauchi, A. Stančáková, G. Andersen, A. Astrup, K. Banasik, A. J. Bennett, L. Bolund, G. Charpentier, Y. Chen, J. M. Dekker, A. S. F. Doney, M. Dorkhan, T. Forsen, T. M. Frayling, C. J. Groves, Y. Gui, G. Hallmans, A. T. Hattersley, K. He, G. A. Hitman, J. Holmkvist, S. Huang, H. Jiang, X. Jin, J. M. Justesen, K. Kristiansen, J. Kuusisto, M. Lajer, O. Lantieri, W. Li, H. Liang, Q. Liao, X. Liu, T. Ma, X. Ma, M. P. Manijak, M. Marre, J. Mokrosiński, A. D. Morris, B. Mu, A. A. Nielsen, G. Nijpels, P. Nilsson, C. N. A. Palmer, N. W. Rayner, F. Renström, R. Ribel-Madsen, N. Robertson, O. Rolandsson, P. Rossing, T. W. Schwartz, P. E. Slagboom, M. Sterner, M. Tang, L. Tarnow, T. Tuomi, E. van’t Riet, N. van Leeuwen, T. V. Varga, M. A. Vestmar, M. Walker, B. Wang, Y. Wang, H. Wu, F. Xi, L. Yengo, C. Yu, X. Zhang, J. Zhang, Q. Zhang, W. Zhang, H. Zheng, Y. Zhou, D. Altshuler, L. M. ‘t Hart, P. W. Franks, B. Balkau, P. Froguel, M. I. McCarthy, M. Laakso, L. Groop, C. Christensen, I. Brandslund, T. Lauritzen, D. R. Witte, A. Linneberg, T. Jørgensen, T. Hansen, J. Wang, R. Nielsen, O. Pedersen
Institutions: University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, BGI Group (China), University of California, Berkeley, Centre for Human Genetics, University of Oxford, Lund University, Centre National de la Recherche Scientifique, University of Eastern Finland, Kuopio University Hospital, Oxford Centre for Diabetes, Endocrinology and Metabolism, Aarhus University, Centre Hospitalier Sud Francilien, Amsterdam Public Health, Amsterdam UMC Location Vrije Universiteit Amsterdam, University of Dundee, Ninewells Hospital, University of Helsinki, Vaasa Central Hospital, University of Exeter, Umeå University, Chinese PLA General Hospital, Queen Mary University of London, Blizard Institute, South China University of Technology, Inserm, Assistance Publique – Hôpitaux de Paris, Hôpital Bichat-Claude-Bernard, Université Paris Diderot, Vejle Sygehus, Skåne University Hospital, Leiden University Medical Center, Helsinki University Hospital, Folkhälsans Forskningscentrum, Newcastle University, Broad Institute, Massachusetts General Hospital, Harvard University, Centre de recherche en Epidémiologie et Santé des Populations, Hammersmith Hospital, Imperial College London, Churchill Hospital, National Institute for Health and Care Research, University of Southern Denmark, Glostrup Hospital, Aalborg University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,490
Funders: Hjerteforeningen, Sundhed og Sygdom, Det Frie Forskningsråd, Villum Fonden, NHS Blood and Transplant, Wellcome Trust, National Institute for Health and Care Research, Diabetes UK, Lundbeckfonden, Kuopion Yliopistollinen Sairaala, Novo Nordisk, Danmarks Frie Forskningsfond, Augustinus Fonden, Region Hovedstaden, Copenhagen Graduate School for Nanoscience and Nanotechnology, Novo Nordisk Fonden, Novo Nordisk Foundation Center for Basic Metabolic Research, H. Lundbeck A/S, Diabetestutkimussäätiö, Diabetesforeningen, Forsknings- og Innovationsstyrelsen, Medical Research Council, Danish Agency for Science and Higher Education
Awards: G2953502109, An investigation of genes in key beta-cell pathways following the type 2 diabetes WTCCC genome wide association study., G3349769430, G3352798684, Statistical methods for the analysis of whole genome association studies., Megakarocyte and Platelet Biology and Genomics, G4411660797, NIHR Senior Investigator Award, G4697006907, G5568298347, NIHR Senior Investigator Award, G616188461, NIHR Senior Investigator Award, G6411832335, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8060355097, The genetics of weight, BMI, adiposity and obesity, G9000069276, G969978795, G970309226
OpenAlex ID: W2110415949