Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

George Hindy¹, Peter Dornbos², Mark D Chaffin³, Dajiang J Liu⁴, Minxian Wang⁵, Margaret Sunitha Selvaraj⁶, David Zhang⁷, Joseph Park⁷, Carlos A Aguilar-Salinas⁸, Lucinda Antonacci-Fulton⁹, Diego Ardissino¹⁰, Donna K Arnett¹¹, Stella Aslibekyan¹², Gil Atzmon¹³, Christie M Ballantyne¹⁴, Francisco Barajas-Olmos¹⁵, Nir Barzilai¹⁶, Lewis C Becker¹⁷, Lawrence F Bielak¹⁸, Joshua C Bis¹⁹, John Blangero²⁰, Eric Boerwinkle²¹, Lori L Bonnycastle²², Erwin Bottinger²³, Donald W Bowden²⁴, Matthew J Bown²⁵, Jennifer A Brody¹⁹, Jai G Broome²⁶, Noël P Burtt²⁷, Brian E Cade²⁸, Federico Centeno-Cruz¹⁵, Edmund Chan²⁹, Yi-Cheng Chang³⁰, Yii-Der I Chen³¹, Ching-Yu Cheng³², Won Jung Choi³³, Rajiv Chowdhury³⁴, Cecilia Contreras-Cubas¹⁵, Emilio J Córdova¹⁵, Adolfo Correa³⁵, L Adrienne Cupples³⁶, Joanne E Curran²⁰, John Danesh³⁷, Paul S de Vries³⁸, Ralph A DeFronzo³⁹, Harsha Doddapaneni⁴⁰, Ravindranath Duggirala²⁰, Susan K Dutcher⁹, Patrick T Ellinor⁴¹, Leslie S Emery²⁶, Jose C Florez⁴², Myriam Fornage⁴³, Barry I Freedman⁴⁴, Valentin Fuster⁴⁵, Ma Eugenia Garay-Sevilla⁴⁶, Humberto García-Ortiz¹⁵, Soren Germer⁴⁷, Richard A Gibbs⁴⁸, Christian Gieger⁴⁹, Benjamin Glaser⁵⁰, Clicerio Gonzalez⁵¹, Maria Elena Gonzalez-Villalpando⁵², Mariaelisa Graff⁵³, Sarah E Graham⁵⁴, Niels Grarup⁵⁵, Leif C Groop⁵⁶, Xiuqing Guo³¹, Namrata Gupta⁵⁷, Sohee Han⁵⁸, Craig L Hanis⁵⁹, Torben Hansen⁶⁰, Jiang He⁶¹, Nancy L Heard-Costa⁶², Yi-Jen Hung⁶³, Mi Yeong Hwang⁵⁸, Marguerite R Irvin⁶⁴, Sergio Islas-Andrade⁶⁵, Gail P Jarvik⁶⁶, Hyun Min Kang⁶⁷, Sharon L R Kardia¹⁸, Tanika Kelly⁶⁸, Eimear E Kenny⁶⁹, Alyna T Khan²⁶, Bong-Jo Kim⁵⁸, Ryan W Kim³³, Young Jin Kim⁵⁸, Heikki A Koistinen⁷⁰, Charles Kooperberg⁷¹, Johanna Kuusisto⁷², Soo Heon Kwak⁷³, Markku Laakso⁷², Leslie A Lange⁷⁴, Jiwon Lee⁷⁵, Juyoung Lee⁵⁸, Seonwook Lee³³, Donna M Lehman³⁹, Rozenn N Lemaitre¹⁹, Allan Linneberg⁷⁶, Jianjun Liu⁷⁷, Ruth J F Loos⁷⁸, Steven A Lubitz⁴¹, Valeriya Lyssenko⁷⁹, Ronald C W Ma⁸⁰, Lisa Warsinger Martin⁸¹, Angélica Martínez-Hernández¹⁵, Rasika A Mathias¹⁷, Stephen T McGarvey⁸², Ruth McPherson⁸³, James B Meigs⁸⁴, Thomas Meitinger⁸⁵, Olle Melander⁸⁶, Elvia Mendoza-Caamal¹⁵, Ginger A Metcalf⁴⁰, Xuenan Mi⁶⁸, Karen L Mohlke⁸⁷, May E Montasser⁸⁸, Jee-Young Moon⁸⁹, Hortensia Moreno-Macías⁹⁰, Alanna C Morrison³⁸, Donna M Muzny⁴⁰, Sarah C Nelson²⁶, Peter M Nilsson⁹¹, Jeffrey R O'Connell⁸⁸, Marju Orho-Melander⁹¹, Lorena Orozco¹⁵, Colin N A Palmer⁹², Nicholette D Palmer²⁴, Cheol Joo Park³³, Kyong Soo Park⁹³, Oluf Pedersen⁵⁵, Juan M Peralta²⁰, Patricia A Peyser¹⁸, Wendy S Post⁹⁴, Michael Preuss⁹⁵, Bruce M Psaty⁹⁶, Qibin Qi⁸⁹, D C Rao⁹⁷, Susan Redline²⁸, Alexander P Reiner⁹⁸, Cristina Revilla-Monsalve⁹⁹, Stephen S Rich¹⁰⁰, Nilesh Samani²⁵, Heribert Schunkert¹⁰¹, Claudia Schurmann¹⁰², Daekwan Seo³³, Jeong-Sun Seo³³, Xueling Sim¹⁰³, Rob Sladek¹⁰⁴, Kerrin S Small¹⁰⁵, Wing Yee So⁸⁰, Adrienne M Stilp²⁶, E Shyong Tai¹⁰⁶, Claudia H T Tam⁸⁰, Kent D Taylor³¹, Yik Ying Teo¹⁰⁷, Farook Thameem¹⁰⁸, Brian Tomlinson¹⁰⁹, Michael Y Tsai¹¹⁰, Tiinamaija Tuomi¹¹¹, Jaakko Tuomilehto¹¹², Teresa Tusié-Luna¹¹³, Miriam S Udler¹¹⁴, Rob M van Dam¹¹⁵, Ramachandran S Vasan¹¹⁶, Karine A Viaud Martinez¹¹⁷, Fei Fei Wang²⁶, Xuzhi Wang¹¹⁸, Hugh Watkins¹¹⁹, Daniel E Weeks¹²⁰, James G Wilson¹²¹, Daniel R Witte¹²², Tien-Yin Wong³², Lisa R Yanek¹⁷; AMP-T2D-GENES, Myocardial Infarction Genetics Consortium; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; NHLBI TOPMed Lipids Working Group; Sekar Kathiresan¹²³, Daniel J Rader¹²⁴, Jerome I Rotter³¹, Michael Boehnke⁶⁷, Mark I McCarthy¹²⁵, Cristen J Willer¹²⁶, Pradeep Natarajan¹²⁷, Jason A Flannick², Amit V Khera³, Gina M Peloso¹²⁸

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
² Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico.
⁹ Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA; The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
¹⁰ ASTC: Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy; Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Universitˆ, degli Studi di Parma, Parma, Italy.
¹¹ Dean's Office, College of Public Health, University of Kentucky, Lexington, KY 40536, USA.
¹² Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
¹³ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; University of Haifa, Faculty of Natural Science, Haifa, Israel.
¹⁴ Houston Methodist Debakey Heart and Vascular Center, Houston, TX 77030, USA; Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
¹⁶ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁸ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 49109, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
²⁰ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
²¹ 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, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
²² Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
²³ Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany.
²⁴ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
²⁵ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²⁶ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
²⁷ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
²⁸ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
²⁹ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore.
³⁰ Institute of Biomedical Sciences, Academia Sinica, Taiwan.
³¹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
³² Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
³³ Psomagen, Inc. (formerly Macrogen USA), 1330 Piccard Drive Ste 103, Rockville, MD 20850, USA.
³⁴ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Centre for Non-Communicable Disease Research, Bangladesh.
³⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; NHLBI Framingham Heart Study, Framingham, MA 01702, USA.
³⁷ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; The National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge, Cambridge, UK.
³⁸ 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, TX 77030, USA.
³⁹ Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
⁴⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴³ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 770030, USA.
⁴⁴ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁴⁵ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
⁴⁶ Department of Medical Science, Division of Health Science, University of Guanajuato, Guanajuanto, Mexico.
⁴⁷ New York Genome Center, New York, NY 10013, USA.
⁴⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁴⁹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁵⁰ Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁵¹ Unidad de Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Pœblica, Cuernavaca, Morelos, Mexico.
⁵² Centro de Estudios en Diabetes, Mexico City, Mexico.
⁵³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁵⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁵⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁶ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Finnish Institute for Molecular Genetics, University of Helsinki, Helsinki, Finland.
⁵⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁵⁸ Division of Genome Science, Department of Precision Medicine, Chungcheongbuk-do, Republic of Korea.
⁵⁹ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁶⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
⁶¹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Tulane University Translational Science Institute, New Orleans, LA 70112, USA.
⁶² NHLBI Framingham Heart Study, Framingham, MA 01702, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
⁶³ Division of Endocrine and Metabolism, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
⁶⁴ Department of Epidemiology, School of Public Health, UAB, Birmingham, AL 35294, USA.
⁶⁵ Dirección de Investigación, Hospital General de México "Dr. Eduardo Liceaga," Secretaría de Salud, Mexico City, Mexico.
⁶⁶ Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA 98195, USA.
⁶⁷ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁶⁸ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
⁶⁹ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷⁰ Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; University of Helsinki and Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
⁷¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98103, USA.
⁷² Institute of Clinical Medicine, University of Eastern Finland, and Kuopio University Hospital, Kuopio, Finland.
⁷³ Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
⁷⁴ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷⁶ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁷ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
⁷⁸ Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷⁹ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; University of Bergen, Bergen, Norway.
⁸⁰ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
⁸¹ Division of Cardiology, Department of Medicine, George Washington University, Washington, DC 20037, USA.
⁸² Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI 02912, USA.
⁸³ Ruddy Canadian Cardiovascuar Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁸⁴ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; General Medicine Division, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸⁵ Deutsches Forschungszentrum fŸr Herz-Kreislauferkrankungen, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁸⁶ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Department of Emergency and Internal Medicine, SkŒne University Hospital, Malmö, Sweden.
⁸⁷ Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
⁸⁸ University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Baltimore, MD 21201, USA.
⁸⁹ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁹⁰ Universidad Autónoma Metropolitana, Mexico City, Mexico.
⁹¹ Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁹² Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
⁹³ Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
⁹⁴ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
⁹⁵ Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98101, USA.
⁹⁷ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63108, USA.
⁹⁸ University of Washington, Seattle, WA 98101, USA.
⁹⁹ Instituto Mexicano del Seguro Social SXXI, Mexico City, Mexico.
¹⁰⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
¹⁰¹ Deutsches Herzzentrum München, Technische UniversitŠt München, Deutsches Zentrum fŸr Herz-Kreislauf-Forschung, München, Germany.
¹⁰² Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany; Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰³ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
¹⁰⁴ Department of Human Genetics, McGill University, Montreal, QC, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
¹⁰⁵ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁰⁶ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Duke-NUS Medical School Singapore, Singapore.
¹⁰⁷ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore.
¹⁰⁸ Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University, Safat, Kuwait.
¹⁰⁹ Faculty of Medicine, Macau University of Science & Technology, Macau, China.
¹¹⁰ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
¹¹¹ Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
¹¹² Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
¹¹³ Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico; Departamento de Medicina Genómica y Toxicología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México/ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
¹¹⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹¹⁵ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
¹¹⁶ NHLBI Framingham Heart Study, Framingham, MA 01702, USA; Departments of Medicine & Epidemiology, Boston University Schools of Medicine & Public Health, Boston, MA 02118, USA.
¹¹⁷ Illumina Laboratory Services, Illumina Inc., San Diego, CA 92122, USA.
¹¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
¹¹⁹ Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹²⁰ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹²¹ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹²² Department of Public Health, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus, Denmark.
¹²³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Verve Therapeutics, Cambridge, MA 02139, USA.
¹²⁴ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹²⁵ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹²⁶ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
¹²⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹²⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. Electronic address: gpeloso@bu.edu.

PMID: 34932938
PMCID: PMC8764201
DOI: 10.1016/j.ajhg.2021.11.021

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

George Hindy et al. Am J Hum Genet. 2022.

. 2022 Jan 6;109(1):81-96.

doi: 10.1016/j.ajhg.2021.11.021. Epub 2021 Dec 20.

Authors

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
² Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico.
⁹ Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA; The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
¹⁰ ASTC: Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy; Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Universitˆ, degli Studi di Parma, Parma, Italy.
¹¹ Dean's Office, College of Public Health, University of Kentucky, Lexington, KY 40536, USA.
¹² Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
¹³ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; University of Haifa, Faculty of Natural Science, Haifa, Israel.
¹⁴ Houston Methodist Debakey Heart and Vascular Center, Houston, TX 77030, USA; Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
¹⁶ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁸ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 49109, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
²⁰ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
²¹ 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, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
²² Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
²³ Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany.
²⁴ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
²⁵ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²⁶ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
²⁷ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
²⁸ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
²⁹ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore.
³⁰ Institute of Biomedical Sciences, Academia Sinica, Taiwan.
³¹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
³² Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
³³ Psomagen, Inc. (formerly Macrogen USA), 1330 Piccard Drive Ste 103, Rockville, MD 20850, USA.
³⁴ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Centre for Non-Communicable Disease Research, Bangladesh.
³⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; NHLBI Framingham Heart Study, Framingham, MA 01702, USA.
³⁷ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; The National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge, Cambridge, UK.
³⁸ 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, TX 77030, USA.
³⁹ Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
⁴⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴³ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 770030, USA.
⁴⁴ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁴⁵ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
⁴⁶ Department of Medical Science, Division of Health Science, University of Guanajuato, Guanajuanto, Mexico.
⁴⁷ New York Genome Center, New York, NY 10013, USA.
⁴⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁴⁹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁵⁰ Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁵¹ Unidad de Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Pœblica, Cuernavaca, Morelos, Mexico.
⁵² Centro de Estudios en Diabetes, Mexico City, Mexico.
⁵³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁵⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁵⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁶ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Finnish Institute for Molecular Genetics, University of Helsinki, Helsinki, Finland.
⁵⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁵⁸ Division of Genome Science, Department of Precision Medicine, Chungcheongbuk-do, Republic of Korea.
⁵⁹ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁶⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
⁶¹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Tulane University Translational Science Institute, New Orleans, LA 70112, USA.
⁶² NHLBI Framingham Heart Study, Framingham, MA 01702, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
⁶³ Division of Endocrine and Metabolism, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
⁶⁴ Department of Epidemiology, School of Public Health, UAB, Birmingham, AL 35294, USA.
⁶⁵ Dirección de Investigación, Hospital General de México "Dr. Eduardo Liceaga," Secretaría de Salud, Mexico City, Mexico.
⁶⁶ Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA 98195, USA.
⁶⁷ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁶⁸ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
⁶⁹ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷⁰ Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; University of Helsinki and Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
⁷¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98103, USA.
⁷² Institute of Clinical Medicine, University of Eastern Finland, and Kuopio University Hospital, Kuopio, Finland.
⁷³ Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
⁷⁴ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷⁶ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁷ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
⁷⁸ Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷⁹ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; University of Bergen, Bergen, Norway.
⁸⁰ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
⁸¹ Division of Cardiology, Department of Medicine, George Washington University, Washington, DC 20037, USA.
⁸² Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI 02912, USA.
⁸³ Ruddy Canadian Cardiovascuar Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁸⁴ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; General Medicine Division, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸⁵ Deutsches Forschungszentrum fŸr Herz-Kreislauferkrankungen, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁸⁶ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Department of Emergency and Internal Medicine, SkŒne University Hospital, Malmö, Sweden.
⁸⁷ Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
⁸⁸ University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Baltimore, MD 21201, USA.
⁸⁹ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁹⁰ Universidad Autónoma Metropolitana, Mexico City, Mexico.
⁹¹ Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁹² Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
⁹³ Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
⁹⁴ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
⁹⁵ Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98101, USA.
⁹⁷ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63108, USA.
⁹⁸ University of Washington, Seattle, WA 98101, USA.
⁹⁹ Instituto Mexicano del Seguro Social SXXI, Mexico City, Mexico.
¹⁰⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
¹⁰¹ Deutsches Herzzentrum München, Technische UniversitŠt München, Deutsches Zentrum fŸr Herz-Kreislauf-Forschung, München, Germany.
¹⁰² Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany; Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰³ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
¹⁰⁴ Department of Human Genetics, McGill University, Montreal, QC, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
¹⁰⁵ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁰⁶ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Duke-NUS Medical School Singapore, Singapore.
¹⁰⁷ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore.
¹⁰⁸ Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University, Safat, Kuwait.
¹⁰⁹ Faculty of Medicine, Macau University of Science & Technology, Macau, China.
¹¹⁰ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
¹¹¹ Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
¹¹² Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
¹¹³ Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico; Departamento de Medicina Genómica y Toxicología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México/ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
¹¹⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹¹⁵ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
¹¹⁶ NHLBI Framingham Heart Study, Framingham, MA 01702, USA; Departments of Medicine & Epidemiology, Boston University Schools of Medicine & Public Health, Boston, MA 02118, USA.
¹¹⁷ Illumina Laboratory Services, Illumina Inc., San Diego, CA 92122, USA.
¹¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
¹¹⁹ Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹²⁰ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹²¹ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹²² Department of Public Health, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus, Denmark.
¹²³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Verve Therapeutics, Cambridge, MA 02139, USA.
¹²⁴ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹²⁵ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹²⁶ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
¹²⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹²⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. Electronic address: gpeloso@bu.edu.

PMID: 34932938
PMCID: PMC8764201
DOI: 10.1016/j.ajhg.2021.11.021

Abstract

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Keywords: association; cholesterol; exome sequencing; gene-based association; lipid.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests for the present work. P.N. reports investigator-initiated grants from Amgen, Apple, and Boston Scientific; is a scientific advisor to Apple, Blackstone Life Sciences, and Novartis; and has spousal employment at Vertex, all unrelated to the present work. A.V.K. has served as a scientific advisor to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color; received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research; and reports a patent related to a genetic risk predictor (20190017119). C.J.W.’s spouse is employed at Regeneron. L.E.S. is currently an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, and interpretation of this study. M.E.M. receives funding from Regeneron unrelated to this work. E.E.K. has received speaker honoraria from Illumina, Inc and Regeneron Pharmaceuticals. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.A.C. has consulted with the Dyslipidemia Foundation on lipid projects in the Framingham Heart Study. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular disease. P.T.E. has consulted for Bayer AG, Novartis, MyoKardia, and Quest Diagnostics. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG, and Blackstone Life Sciences. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.M. has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global and has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. M.E.J. holds shares in Novo Nordisk A/S. H.M.K. is an employee of Regeneron Pharmaceuticals; he owns stock and stock options for Regeneron Pharmaceuticals. M.E.J. has received research grants form Astra Zeneca, Boehringer Ingelheim, Amgen, and Sanofi. S.K. is founder of Verve Therapeutics.

Figures

**Figure 1**
Study samples and design Flow chart of the different stages of the study. Exome sequence genotypes were derived from four major data sources: the Myocardial Infarction Genetics consortium (MIGen), the Trans-Omics from Precision Medicine (TOPMed), the UK Biobank, and the Type 2 Diabetes Genetics (AMP-T2D-GENES) consortium. Single-variant association analyses were performed by ancestry and case status in case-control studies and meta-analyzed. Single-variant summary estimates and covariance matrices were used in gene-based analyses with six different variant groups and in multi-ancestry and each of the five main ancestries. AFR, African ancestry; EAS, East Asian ancestry; EUR, European ancestry; HIS, Hispanic ancestry; SAM, Samoan ancestry; SAS, South Asian ancestry.

**Figure 2**
Exome-wide significant associations with blood lipid phenotypes (A) Circular plot highlighting the evidence of association between the exome-wide significant 35 genes with any of the six different lipid traits (p < 4.3 × 10⁻⁷). The most significant associations from any of the six different variant groups are plotted. For almost all of the genes, the most significant associations were obtained from the multi-ancestry meta-analysis. (B) Strength of association of the 35 exome-wide significant genes based on the most significant variant grouping and ancestry across the six lipid phenotypes studied. Beta (effect size) is obtained from the corresponding burden test for SKAT results. Most of the genes indicated associations with more than one phenotype. Sign(beta)^∗−log10(p value) displayed for associations that reached a p < 4.3 × 10⁻⁷. When the Sign(beta)^∗−log10(p) > 50, they were trimmed to 50.

**Figure 3**
Enrichment of Mendelian, GWAS, and drug target genes in the gene-based lipid associations Enrichment of gene sets of Mendelian genes (n = 21), GWAS loci for LDL-C (n = 487), HDL-C (n = 531), and triglycerides (TG) (n = 471) genes, and drug target genes (n = 53). Error bars denote 95% confidence intervals.

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References

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Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

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Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

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