Exome-wide association study of plasma lipids in >300,000 individuals

doi:10.1038/ng.3977

. 2017 Dec;49(12):1758-1766.

doi: 10.1038/ng.3977. Epub 2017 Oct 30.

Exome-wide association study of plasma lipids in >300,000 individuals

Dajiang J Liu¹, Gina M Peloso^{2

3}, Haojie Yu⁴, Adam S Butterworth^{5

6}, Xiao Wang⁷, Anubha Mahajan⁸, Danish Saleheen^{5

9

10}, Connor Emdin^{3

11}, Dewan Alam¹², Alexessander Couto Alves¹³, Philippe Amouyel¹⁴, Emanuele Di Angelantonio^{5

6}, Dominique Arveiler¹⁵, Themistocles L Assimes^{16

17}, Paul L Auer¹⁸, Usman Baber¹⁹, Christie M Ballantyne²⁰, Lia E Bang²¹, Marianne Benn^{22

23}, Joshua C Bis²⁴, Michael Boehnke²⁵, Eric Boerwinkle^{26

27}, Jette Bork-Jensen²⁸, Erwin P Bottinger²⁹, Ivan Brandslund^{30

31}, Morris Brown³², Fabio Busonero³³, Mark J Caulfield^{32

34

35}, John C Chambers^{36

37

38}, Daniel I Chasman^{39

40}, Y Eugene Chen⁴¹, Yii-Der Ida Chen⁴², Rajiv Chowdhury⁵, Cramer Christensen⁴³, Audrey Y Chu^{39

44}, John M Connell⁴⁵, Francesco Cucca^{33

46}, L Adrienne Cupples^{2

44}, Scott M Damrauer^{47

48}, Gail Davies^{49

50}, Ian J Deary^{49

50}, George Dedoussis⁵¹, Joshua C Denny^{52

53}, Anna Dominiczak⁵⁴, Marie-Pierre Dubé^{55

56

57}, Tapani Ebeling⁵⁸, Gudny Eiriksdottir⁵⁹, Tõnu Esko^{3

60}, Aliki-Eleni Farmaki⁵¹, Mary F Feitosa⁶¹, Marco Ferrario⁶², Jean Ferrieres⁶³, Ian Ford⁶⁴, Myriam Fornage⁶⁵, Paul W Franks^{66

67

68}, Timothy M Frayling⁶⁹, Ruth Frikke-Schmidt^{22

23}, Lars G Fritsche²⁵, Philippe Frossard¹⁰, Valentin Fuster^{19

70}, Santhi K Ganesh^{41

71}, Wei Gao⁷², Melissa E Garcia⁷³, Christian Gieger^{74

75

76}, Franco Giulianini³⁹, Mark O Goodarzi^{77

78}, Harald Grallert^{74

75

76}, Niels Grarup²⁸, Leif Groop⁷⁹, Megan L Grove²⁶, Vilmundur Gudnason^{59

80}, Torben Hansen^{28

81}, Tamara B Harris⁸², Caroline Hayward⁸³, Joel N Hirschhorn^{3

84}, Oddgeir L Holmen^{85

86}, Jennifer Huffman⁸³, Yong Huo⁸⁷, Kristian Hveem⁸⁸, Sehrish Jabeen¹⁰, Anne U Jackson²⁵, Johanna Jakobsdottir^{59

89}, Marjo-Riitta Jarvelin¹³, Gorm B Jensen⁹⁰, Marit E Jørgensen^{91

92}, J Wouter Jukema^{93

94}, Johanne M Justesen²⁸, Pia R Kamstrup⁹⁵, Stavroula Kanoni⁹⁶, Fredrik Karpe^{97

98}, Frank Kee⁹⁹, Amit V Khera^{3

11}, Derek Klarin^{3

11

100}, Heikki A Koistinen^{101

102

103}, Jaspal S Kooner^{37

38

104}, Charles Kooperberg¹⁰⁵, Kari Kuulasmaa¹⁰¹, Johanna Kuusisto¹⁰⁶, Markku Laakso¹⁰⁶, Timo Lakka^{107

108

109}, Claudia Langenberg¹¹⁰, Anne Langsted^{95

111}, Lenore J Launer⁸², Torsten Lauritzen¹¹², David C M Liewald^{49

50}, Li An Lin⁶⁵, Allan Linneberg^{113

114

115}, Ruth J F Loos^{29

116}, Yingchang Lu²⁹, Xiangfeng Lu^{41

117}, Reedik Mägi⁶⁰, Anders Malarstig^{118

119}, Ani Manichaikul¹²⁰, Alisa K Manning^{3

11

121}, Pekka Mäntyselkä¹²², Eirini Marouli⁹⁶, Nicholas G D Masca^{123

124}, Andrea Maschio³³, James B Meigs^{3

121

125}, Olle Melander¹²⁶, Andres Metspalu⁶⁰, Andrew P Morris^{8

127}, Alanna C Morrison²⁶, Antonella Mulas³³, Martina Müller-Nurasyid^{76

128

129}, Patricia B Munroe^{32

35}, Matt J Neville⁹⁷, Jonas B Nielsen⁴¹, Sune F Nielsen^{95

111}, Børge G Nordestgaard^{95

111}, Jose M Ordovas^{130

131

132}, Roxana Mehran¹⁹, Christoper J O'Donnell^{100

40}, Marju Orho-Melander¹²⁶, Cliona M Molony¹³³, Pieter Muntendam¹³⁴, Sandosh Padmanabhan⁵⁴, Colin N A Palmer⁴⁵, Dorota Pasko⁶⁹, Aniruddh P Patel^{3

11

40

135}, Oluf Pedersen²⁸, Markus Perola^{101

136}, Annette Peters^{74

76

129}, Charlotta Pisinger¹¹⁵, Giorgio Pistis³³, Ozren Polasek^{137

138}, Neil Poulter¹³⁹, Bruce M Psaty^{24

140

141}, Daniel J Rader¹⁴², Asif Rasheed¹⁰, Rainer Rauramaa^{108

109}, Dermot F Reilly¹³³, Alex P Reiner^{105

143}, Frida Renström^{66

144}, Stephen S Rich¹²⁰, Paul M Ridker³⁹, John D Rioux⁵⁵, Neil R Robertson^{8

97}, Dan M Roden^{52

53}, Jerome I Rotter⁴², Igor Rudan¹³⁸, Veikko Salomaa¹⁰¹, Nilesh J Samani^{123

124}, Serena Sanna³³, Naveed Sattar^{54

97}, Ellen M Schmidt¹⁴⁵, Robert A Scott¹¹⁰, Peter Sever¹³⁹, Raquel S Sevilla¹⁴⁶, Christian M Shaffer⁵³, Xueling Sim^{25

147}, Suthesh Sivapalaratnam¹⁴⁸, Kerrin S Small¹⁴⁹, Albert V Smith^{59

80}, Blair H Smith^{150

151}, Sangeetha Somayajula¹⁵², Lorraine Southam^{8

153}, Timothy D Spector¹⁴⁹, Elizabeth K Speliotes^{145

154}, John M Starr^{49

155}, Kathleen E Stirrups^{96

156}, Nathan Stitziel^{157

158}, Konstantin Strauch^{159

160}, Heather M Stringham²⁵, Praveen Surendran⁵, Hayato Tada¹⁶¹, Alan R Tall¹⁶², Hua Tang¹⁶³, Jean-Claude Tardif^{55

57}, Kent D Taylor⁴², Stella Trompet^{93

164}, Philip S Tsao^{16

17}, Jaakko Tuomilehto^{165

166

167

168}, Anne Tybjaerg-Hansen^{22

23}, Natalie R van Zuydam^{8

45}, Anette Varbo^{95

111}, Tibor V Varga⁶⁶, Jarmo Virtamo¹⁰¹, Melanie Waldenberger^{75

76

129}, Nan Wang¹⁶², Nick J Wareham¹¹⁰, Helen R Warren^{32

35}, Peter E Weeke^{53

169}, Joshua Weinstock²⁵, Jennifer Wessel^{170

171}, James G Wilson¹⁷², Peter W F Wilson^{173

174}, Ming Xu¹⁷⁵, Hanieh Yaghootkar⁶⁹, Robin Young⁵, Eleftheria Zeggini¹⁵³, He Zhang⁴¹, Neil S Zheng¹⁷⁶, Weihua Zhang³⁶, Yan Zhang⁸⁷, Wei Zhou¹⁴⁵, Yanhua Zhou², Magdalena Zoledziewska³³; Charge Diabetes Working Group; EPIC-InterAct Consortium; EPIC-CVD Consortium; GOLD Consortium; VA Million Veteran Program; Joanna M M Howson⁵, John Danesh^{5

6

153}, Mark I McCarthy^{8

97

98}, Chad A Cowan^{4

177}, Goncalo Abecasis²⁵, Panos Deloukas^{96

178}, Kiran Musunuru⁷, Cristen J Willer^{41

71

145}, Sekar Kathiresan^{3

11

40

135}

Affiliations

¹ Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.
² Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
³ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
⁴ Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
⁵ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK.
⁷ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁹ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Center for Non-Communicable Diseases, Karachi, Pakistan.
¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹² ICDDR, B, Dhaka, Bangladesh.
¹³ Imperial College London, London, UK.
¹⁴ Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France.
¹⁵ Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France.
¹⁶ VA Palo Alto Health Care System, Palo Alto, California, USA.
¹⁷ Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹⁸ Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
¹⁹ Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
²¹ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²² Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
²³ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
²⁵ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
²⁶ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁷ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
²⁸ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁹ The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
³⁰ Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
³¹ Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
³² Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
³³ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
³⁴ The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK.
³⁵ NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
³⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁷ Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK.
³⁸ Imperial College Healthcare NHS Trust, London, UK.
³⁹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁴⁰ Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
⁴¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁴² The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA.
⁴³ Medical Department, Lillebaelt Hospital, Vejle, Denmark.
⁴⁴ NHLBI Framingham Heart Study, Framingham, Massachusetts, USA.
⁴⁵ Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁴⁶ Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
⁴⁷ Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA.
⁴⁸ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁵⁰ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁵¹ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
⁵² Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁵³ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁵⁴ British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁵⁵ Montreal Heart Institute, Montreal, Quebec, Canada.
⁵⁶ Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada.
⁵⁷ Université de Montréal, Montreal, Quebec, Canada.
⁵⁸ Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland.
⁵⁹ The Icelandic Heart Association, Kopavogur, Iceland.
⁶⁰ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁶¹ Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
⁶² Research Centre in Epidemiology and Preventive Medicine-EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
⁶³ Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, Toulouse, France.
⁶⁴ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁶⁵ Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁶⁶ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
⁶⁷ Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.
⁶⁸ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
⁶⁹ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
⁷⁰ Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
⁷¹ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
⁷² Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China.
⁷³ National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
⁷⁴ German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
⁷⁵ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁶ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁷ Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷⁸ Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷⁹ Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden.
⁸⁰ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸¹ Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
⁸² Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.
⁸³ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁸⁴ Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.
⁸⁵ Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway.
⁸⁶ St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸⁷ Department of Cardiology, Peking University First Hospital, Beijing, China.
⁸⁸ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁸⁹ Department of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁹⁰ The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark.
⁹¹ Steno Diabetes Center, Gentofte, Denmark.
⁹² National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark.
⁹³ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁴ The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
⁹⁵ Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
⁹⁶ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹⁷ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁹⁸ Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
⁹⁹ UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK.
¹⁰⁰ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA.
¹⁰¹ Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰² Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
¹⁰³ Minerva Foundation Institute for Medical Research, Helsinki, Finland.
¹⁰⁴ National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.
¹⁰⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁰⁶ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹⁰⁷ Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
¹⁰⁸ Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
¹⁰⁹ Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
¹¹⁰ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹¹¹ Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark.
¹¹² Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark.
¹¹³ Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
¹¹⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹⁵ Research Center for Prevention and Health, Copenhagen, Denmark.
¹¹⁶ The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
¹¹⁷ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹¹⁸ Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
¹¹⁹ Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden.
¹²⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹²¹ Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹²² Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹²³ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
¹²⁴ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
¹²⁵ Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹²⁶ Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
¹²⁷ Department of Biostatistics, University of Liverpool, Liverpool, UK.
¹²⁸ Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany.
¹²⁹ DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany.
¹³⁰ Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain.
¹³¹ IMDEA-Alimentacion, Madrid, Spain.
¹³² Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
¹³³ Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.
¹³⁴ G3 Pharmaceuticals, Lexington, Massachusetts, USA.
¹³⁵ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹³⁶ Institute of Molecular Medicine FIMM, University of Helsinki, Finland.
¹³⁷ Faculty of Medicine, University of Split, Split, Croatia.
¹³⁸ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
¹³⁹ International Centre for Circulatory Health, Imperial College London, London, UK.
¹⁴⁰ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
¹⁴¹ Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.
¹⁴² Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁴³ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁴⁴ Department of Biobank Research, Umeå University, Umeå, Sweden.
¹⁴⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
¹⁴⁶ Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.
¹⁴⁷ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
¹⁴⁸ Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
¹⁴⁹ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁵⁰ Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
¹⁵¹ Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
¹⁵² Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.
¹⁵³ Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
¹⁵⁴ Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
¹⁵⁵ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
¹⁵⁶ Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁵⁷ Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁵⁸ The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁵⁹ IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany.
¹⁶⁰ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶¹ Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
¹⁶² Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA.
¹⁶³ Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
¹⁶⁴ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶⁵ Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
¹⁶⁶ Dasman Diabetes Institute, Dasman, Kuwait.
¹⁶⁷ Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
¹⁶⁸ Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia.
¹⁶⁹ The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁷⁰ Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA.
¹⁷¹ Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁷² Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
¹⁷³ Atlanta VA Medical Center, Decatur, Georgia, USA.
¹⁷⁴ Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA.
¹⁷⁵ Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
¹⁷⁶ Yale College, Yale University, New Haven, Connecticut, USA.
¹⁷⁷ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁷⁸ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 29083408
PMCID: PMC5709146
DOI: 10.1038/ng.3977

Exome-wide association study of plasma lipids in >300,000 individuals

Dajiang J Liu et al. Nat Genet. 2017 Dec.

. 2017 Dec;49(12):1758-1766.

doi: 10.1038/ng.3977. Epub 2017 Oct 30.

Authors

Affiliations

¹ Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.
² Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
³ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
⁴ Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
⁵ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK.
⁷ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁹ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Center for Non-Communicable Diseases, Karachi, Pakistan.
¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹² ICDDR, B, Dhaka, Bangladesh.
¹³ Imperial College London, London, UK.
¹⁴ Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France.
¹⁵ Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France.
¹⁶ VA Palo Alto Health Care System, Palo Alto, California, USA.
¹⁷ Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹⁸ Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
¹⁹ Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
²¹ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²² Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
²³ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
²⁵ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
²⁶ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁷ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
²⁸ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁹ The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
³⁰ Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
³¹ Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
³² Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
³³ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
³⁴ The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK.
³⁵ NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
³⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁷ Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK.
³⁸ Imperial College Healthcare NHS Trust, London, UK.
³⁹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁴⁰ Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
⁴¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁴² The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA.
⁴³ Medical Department, Lillebaelt Hospital, Vejle, Denmark.
⁴⁴ NHLBI Framingham Heart Study, Framingham, Massachusetts, USA.
⁴⁵ Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁴⁶ Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
⁴⁷ Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA.
⁴⁸ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁵⁰ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁵¹ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
⁵² Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁵³ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁵⁴ British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁵⁵ Montreal Heart Institute, Montreal, Quebec, Canada.
⁵⁶ Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada.
⁵⁷ Université de Montréal, Montreal, Quebec, Canada.
⁵⁸ Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland.
⁵⁹ The Icelandic Heart Association, Kopavogur, Iceland.
⁶⁰ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁶¹ Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
⁶² Research Centre in Epidemiology and Preventive Medicine-EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
⁶³ Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, Toulouse, France.
⁶⁴ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁶⁵ Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁶⁶ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
⁶⁷ Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.
⁶⁸ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
⁶⁹ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
⁷⁰ Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
⁷¹ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
⁷² Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China.
⁷³ National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
⁷⁴ German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
⁷⁵ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁶ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁷ Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷⁸ Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷⁹ Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden.
⁸⁰ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸¹ Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
⁸² Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.
⁸³ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁸⁴ Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.
⁸⁵ Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway.
⁸⁶ St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸⁷ Department of Cardiology, Peking University First Hospital, Beijing, China.
⁸⁸ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁸⁹ Department of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁹⁰ The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark.
⁹¹ Steno Diabetes Center, Gentofte, Denmark.
⁹² National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark.
⁹³ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁴ The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
⁹⁵ Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
⁹⁶ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹⁷ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁹⁸ Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
⁹⁹ UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK.
¹⁰⁰ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA.
¹⁰¹ Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰² Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
¹⁰³ Minerva Foundation Institute for Medical Research, Helsinki, Finland.
¹⁰⁴ National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.
¹⁰⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁰⁶ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹⁰⁷ Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
¹⁰⁸ Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
¹⁰⁹ Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
¹¹⁰ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹¹¹ Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark.
¹¹² Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark.
¹¹³ Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
¹¹⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹⁵ Research Center for Prevention and Health, Copenhagen, Denmark.
¹¹⁶ The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
¹¹⁷ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹¹⁸ Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
¹¹⁹ Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden.
¹²⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹²¹ Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹²² Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹²³ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
¹²⁴ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
¹²⁵ Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹²⁶ Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
¹²⁷ Department of Biostatistics, University of Liverpool, Liverpool, UK.
¹²⁸ Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany.
¹²⁹ DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany.
¹³⁰ Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain.
¹³¹ IMDEA-Alimentacion, Madrid, Spain.
¹³² Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
¹³³ Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.
¹³⁴ G3 Pharmaceuticals, Lexington, Massachusetts, USA.
¹³⁵ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹³⁶ Institute of Molecular Medicine FIMM, University of Helsinki, Finland.
¹³⁷ Faculty of Medicine, University of Split, Split, Croatia.
¹³⁸ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
¹³⁹ International Centre for Circulatory Health, Imperial College London, London, UK.
¹⁴⁰ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
¹⁴¹ Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.
¹⁴² Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁴³ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁴⁴ Department of Biobank Research, Umeå University, Umeå, Sweden.
¹⁴⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
¹⁴⁶ Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.
¹⁴⁷ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
¹⁴⁸ Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
¹⁴⁹ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁵⁰ Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
¹⁵¹ Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
¹⁵² Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA.
¹⁵³ Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
¹⁵⁴ Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
¹⁵⁵ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
¹⁵⁶ Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁵⁷ Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁵⁸ The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁵⁹ IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany.
¹⁶⁰ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶¹ Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
¹⁶² Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA.
¹⁶³ Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
¹⁶⁴ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶⁵ Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
¹⁶⁶ Dasman Diabetes Institute, Dasman, Kuwait.
¹⁶⁷ Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
¹⁶⁸ Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia.
¹⁶⁹ The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁷⁰ Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA.
¹⁷¹ Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁷² Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
¹⁷³ Atlanta VA Medical Center, Decatur, Georgia, USA.
¹⁷⁴ Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA.
¹⁷⁵ Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
¹⁷⁶ Yale College, Yale University, New Haven, Connecticut, USA.
¹⁷⁷ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁷⁸ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 29083408
PMCID: PMC5709146
DOI: 10.1038/ng.3977

Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

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Figures

**Figure 1. A1CF p.Gly398Ser mutant leads to increased APOB100 secretion**
a, Western blot showing the depletion of endogenous A1CF levels via CRISPR/Cas9 system in both Huh7 and HepG2 cells. b and c, Lack of A1CF leads to reduced APOB100 secretion in Huh7 (b) and HepG2 (c) human hepatoma cells. d, Recombinantly overexpressed A1CF p.Gly398Ser variant led to significantly increased APOB100 secretion compared to A1CF or GFP control in both Huh7 wild-type and A1CF knockout cells (labeled as A1CF KO), respectively. The bars of mean value and error bars of SD are showed in b, c and d from experiments with biological replicates, N=6. Statistically significant differences are marked (*p<0.05, **p<0.01).

**Figure 2. Association of genetically-lowered triglycerides by *LPL* variants with a range of phenotypes**
Estimates were derived in UK Biobank using logistic regression, adjusting for age, sex, ten principal components of ancestry and an indicator variable for array type. Effect estimates are for a 1 standard deviation lower plasma triglycerides. Definitions for all outcomes are provided in Supplementary Table 20.

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References

1. Loh PR, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47:284–90. - PMC - PubMed
1. Teslovich TM, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13. - PMC - PubMed
1. Asselbergs FW, et al. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet. 2012;91:823–38. - PMC - PubMed
1. Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83. - PMC - PubMed
1. Albrechtsen A, et al. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia. 2013;56:298–310. - PMC - PubMed

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[1] Loh PR, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47:284–90. - PMC - PubMed

[2] Loh PR, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47:284–90. - PMC - PubMed

[3] Teslovich TM, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13. - PMC - PubMed

[4] Teslovich TM, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13. - PMC - PubMed

[5] Asselbergs FW, et al. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet. 2012;91:823–38. - PMC - PubMed

[6] Asselbergs FW, et al. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet. 2012;91:823–38. - PMC - PubMed

[7] Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83. - PMC - PubMed

[8] Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83. - PMC - PubMed

[9] Albrechtsen A, et al. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia. 2013;56:298–310. - PMC - PubMed

[10] Albrechtsen A, et al. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia. 2013;56:298–310. - PMC - PubMed

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Exome-wide association study of plasma lipids in >300,000 individuals

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Exome-wide association study of plasma lipids in >300,000 individuals

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