title: Analysis with the exome array identifies multiple new independent variants in lipid loci.
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.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kanoni
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
authors.forename: Nicholas G D
authors.initials: NG
authors.lastname: Masca
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Stirrups
authors.affiliation: The Broad Institute of MIT and Harvard, Boston, MA 02142, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: Tibor V
authors.initials: TV
authors.lastname: Varga
authors.affiliation: Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Warren
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.|Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.|Ealing Hospital NHS Trust, Middlesex, UK.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.|Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.affiliation: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
authors.forename: Alexessander
authors.initials: A
authors.lastname: Couto Alves
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Lazaros
authors.initials: L
authors.lastname: Lataniotis
authors.affiliation: Section of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Nikman
authors.initials: N
authors.lastname: An Hashim
authors.affiliation: CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Besse
authors.affiliation: CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.affiliation: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
authors.affiliation: Division of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Western Infirmary, Glasgow, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Dominiczak
authors.affiliation: Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University Athens, Athens, Greece.
authors.forename: Aliki-Eleni
authors.initials: AE
authors.lastname: Farmaki
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Institute of Reproductive and Developmental Biology, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Franks
authors.affiliation: 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.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden.
authors.forename: Jan-Håkan
authors.initials: JH
authors.lastname: Jansson
authors.affiliation: Echinos Medical Centre, Echinos, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karaleftheri
authors.affiliation: Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors.forename: Sirkka
authors.initials: S
authors.lastname: Keinänen-Kiukaanniemi
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Matchan
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Dorota
authors.initials: D
authors.lastname: Pasko
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: International Centre for Circulatory Health, Imperial College London, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Poulter
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.|Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Rayner
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.|Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Renström
authors.affiliation: Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Rolandsson
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Sabater-Lleal
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Sennblad
authors.affiliation: International Centre for Circulatory Health, Imperial College London, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Sever
authors.affiliation: Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Denis
authors.initials: D
authors.lastname: Shields
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.affiliation: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Stephens Green, Dublin, Ireland.
authors.forename: Alice V
authors.initials: AV
authors.lastname: Stanton
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.affiliation: Anogia Medical Centre, Anogia, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Tsafantakis
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Section of Investigative Medicine, Imperial College London, London, UK.|Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
authors.affiliation: Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Escher
authors.affiliation: Ealing Hospital NHS Trust, Middlesex, UK.|Imperial College Healthcare NHS Trust, London, UK.|National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.affiliation: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.|Institute of Health Sciences, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Oulu, Finland.|Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: 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.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.|Ealing Hospital NHS Trust, Middlesex, UK.|Imperial College Healthcare NHS Trust, London, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.affiliation: Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.|Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.|Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK p.deloukas@qmul.ac.uk.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK p.deloukas@qmul.ac.uk.|Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D044465:White People
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D014280:Triglycerides