Year: 2016
Type: article
Study design: Observational Study
Abstract: It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddw227
Authors: Stavroula Kanoni, Nicholas G.D. Masca, Kathleen E. Stirrups, Tibor V. Varga, Helen R. Warren, Robert A. Scott, Lorraine Southam, Weihua Zhang, Hanieh Yaghootkar, Martina Müller-Nurasyid, Alexessander Couto Alves, Rona J. Strawbridge, Lazaros Lataniotis, Nikman An Hashim, Céline Besse, Anne Boland, Peter S. Braund, John M. Connell, Anna Dominiczak, Aliki-Eleni Farmaki, Stephen Franks, Harald Grallert, Jan-Håkan Jansson, Maria Karaleftheri, Sirkka Keinänen-Kiukaanniemi, Angela Matchan, Dorota Pasko, Annette Peters, Neil Poulter, Nigel W. Rayner, Frida Renström, Olov Rolandsson, Maria Sabater-Lleal, Bengt Sennblad, Peter Sever, Denis Shields, Angela Silveira, Alice V. Stanton, Konstantin Strauch, Maciej Tomaszewski, Emmanouil Tsafantakis, Melanie Waldenberger, Alexandra I.F. Blakemore, George Dedoussis, Stefan A. Escher, Jaspal S. Kooner, Mark I. McCarthy, Colin N.A. Palmer, Anders Hamsten, Mark J. Caulfield, Timothy M. Frayling, Martin D. Tobin, Marjo-Riitta Jarvelin, Eleftheria Zeggini, Christian Gieger, John C. Chambers, Nick J. Wareham, Patricia B. Munroe, Paul W. Franks, Nilesh J. Samani, Panos Deloukas
Institutions: Queen Mary University of London, William Harvey Research Institute, University of Leicester, Glenfield Hospital, NIHR Leicester Cardiovascular Biomedical Research Unit, Wellcome Sanger Institute, Broad Institute, Lund University, Massachusetts General Hospital, Skåne University Hospital, NIHR Barts Cardiovascular Biomedical Research Unit, Addenbrooke's Hospital, MRC Epidemiology Unit, Medical Research Council, Centre for Human Genetics, Ealing Hospital NHS Trust, Imperial College London, University of Exeter, Helmholtz Munich, German Centre for Cardiovascular Research, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, MRC Centre for Environment and Health, Karolinska Institutet, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, University of Dundee, Ninewells Hospital, Western Infirmary, University of Glasgow, Harokopio University of Athens, German Center for Diabetes Research, Umeå University, University of Oulu, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Science for Life Laboratory, University College Dublin, Royal College of Surgeons in Ireland, Brunel University of London, Imperial College Healthcare NHS Trust, Churchill Hospital, Oulu University Hospital, Finnish Institute for Health and Welfare, Harvard University, University Hospital of Umeå, King Abdulaziz University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Pfizer, Torsten Söderbergs Stiftelse, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, Stiftelsen för Gamla Tjänarinnor, Swedish e-Science Research Centre, National Institute for Health and Care Research, British Heart Foundation, Imperial College London, Imperial College Healthcare NHS Trust, European Commission, Bundesministerium für Bildung und Forschung, Hjärt-Lungfonden, Karolinska Institutet, Stockholms Läns Landsting, Vetenskapsrådet, Oulun Yliopisto, Magnus Bergvalls Stiftelse, Servier, National Institutes of Health, Medical Research Council, Helmholtz Zentrum München, Münchner Zentrum für Gesundheitswissenschaften, Biocenter, University of Oulu, National Heart, Lung, and Blood Institute, National Institute of Mental Health
Awards: G1044594144, G1137313802, European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing, G178033515, G2064885621, G208753423, G2107972360, Identification of epigenetic markers underlying increased risk of T2D in South Asians, WTCCC2 core activities, G2824707892, Collaborative strategy for a definitive genome scan in essential hypertension: high fidelity phenotyping and ‘hypercontrols’, G3294462333, Genetic Influences on ADHD in a Finnish Birth Cohort, G3316531930, G3349769430, G3367174484, G3445821079, G3520205971, NIHR Senior Investigator Award, G3812975344, G3814398992, G385201875, G4050880153, G4209859223, G4515475997, G459060772, European Network for Genetic and Genomic Epidemiology, G4735382418, G4805552703, G4839860845, RENEWAL: Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies, G4975632709, G5087288417, Genetics of cardiovascular risk factors in large founder population birth control, NIHR Senior Investigator Award, G5404300429, G5502349062, G5568298347, A national DNA control series for genetic case-control studies based on the British 1958 birth cohort, G5810988395, NIHR Senior Investigator Award, G6154452564, Whole Genome Assoc. Analysis Strategies for Multi. Phenotypes, G6323180499, G6421092503, G6518651994, G6519421474, G6562605244, G6661414329, Identification of genetic variants underlying coronary artery disease and associated phenotypes in Indian Asians., G6815174083, G6957823285, G7154858182, G7333372387, G7549694323, G7627314639, G76861965, Derivation and validation of a risk model for prediction of cardiovascular disease events in UK Indian Asians, G8303984992, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G8769285145, Genomics of coronary arthery disease. ,, G8937465282, NIHR Senior Investigator Award
OpenAlex ID: W2484527815