Ron Do^1,2,3,4*, Nathan O. Stitziel^5,6*, Hong-Hee Won^1,2,3,4*, Anders Berg Jørgensen⁷, Stefano Duga⁸, Pier Angelica Merlini⁹, Adam Kiezun⁴, Martin Farrall¹⁰, Anuj Goel¹⁰, Or Zuk⁴, Illaria Guella⁸, Rosanna Asselta⁸, Leslie A. Lange¹¹, Gina M. Peloso^1,2,3,4, Paul L. Auer¹², NHLBI Exome Sequencing Project^†, Domenico Girelli¹³, Nicola Martinelli¹³, Deborah N. Farlow⁴, Mark A. DePristo⁴, Robert Roberts¹⁴, Alexander F. R. Stewart¹⁴, Danish Saleheen¹⁵, John Danesh¹⁵, Stephen E. Epstein¹⁶, Suthesh Sivapalaratnam¹⁷, G. Kees Hovingh¹⁷, John J. Kastelein¹⁷, Nilesh J. Samani¹⁸, Heribert Schunkert¹⁹, Jeanette Erdmann²⁰, Svati H. Shah^21,22, William E. Kraus²², Robert Davies²³, Majid Nikpay²³, Christopher T. Johansen²⁴, Jian Wang²⁴, Robert A. Hegele^24,25, Eliana Hechter⁴, Winfried Marz^26,27,28, Marcus E. Kleber²⁶, Jie Huang²⁹, Andrew D.Johnson³⁰, Mingyao Li³¹, Greg L. Burke³², Myron Gross³³, Yongmei Liu³⁴, Themistocles L. Assimes³⁵, Gerardo Heiss³⁶, Ethan M. Lange^11,37, Aaron R. Folsom³⁸, Herman A. Taylor³⁹, Oliviero Olivieri¹³, Anders Hamsten⁴⁰, Robert Clarke⁴¹, Dermot F. Reilly⁴², Wu Yin⁴², Manuel A. Rivas⁴³, Peter Donnelly^43,44, Jacques E. Rossouw⁴⁵, Bruce M. Psaty^46,47, David M. Herrington⁴⁸, James G. Wilson⁴⁹, Stephen S. Rich⁵⁰, Michael J. Bamshad^51,52,53, Russell P. Tracy⁵⁴, L. Adrienne Cupples⁵⁵, Daniel J. Rader⁵⁶, Muredach P. Reilly⁵⁷, John A. Spertus⁵⁸, Sharon Cresci^5,59, Jaana Hartiala⁶⁰, W. H. Wilson Tang⁶¹, Stanley L. Hazen⁶¹, Hooman Allayee⁶⁰, Alex P. Reiner^12,62, Christopher S. Carlson¹², Charles Kooperberg¹², Rebecca D. Jackson63, Eric Boerwinkle⁶⁴, Eric S. Lander⁴, Stephen M. Schwartz^12,62, David S. Siscovick^62,65, Ruth McPherson²³, Anne Tybjaerg-Hansen^7,66, Goncalo R. Abecasis⁶⁷, Hugh Watkins^10,43, Deborah A. Nickerson⁵³, Diego Ardissino⁶⁸, Shamil R. Sunyaev^4,69, Christopher J. O’Donnell²⁹, David Altshuler^1,4, Stacey Gabriel4 & Sekar Kathiresan^1,2,3,4

¹Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ²Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA ³Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. ⁴Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ⁵Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. ⁶Division of Statistical Genomics, Washington University School of Medicine, St Louis, Missouri 63110, USA. ⁷Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark. ⁸Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Universita` degli Studi di Milano, Milano 20122, Italy. ⁹Division of Cardiology, Ospedale Niguarda, Milano 20162, Italy. ¹⁰Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2J, UK. ¹¹Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ¹²Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ¹³University of Verona School of Medicine, Department of Medicine, Verona 37129, Italy. ¹⁴John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario K1Y4W7, Canada. ¹⁵Department of Public Health and Primary Care,University of Cambridge, Cambridge CB2 1TN, UK. ¹⁶MedStar Health Research Institute, Cardiovascular Research Institute, Hyattsville, Maryland 20782, USA. ¹⁷Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands. ¹⁸Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK. ¹⁹DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Berlin 13347, Germany. ²⁰Medizinische Klinik II, University of Lu¨beck, Lu¨beck 23562, Germany. ²¹Center for Human Genetics, Duke University, Durham, North Carolina 27708, USA. ²²Department of Cardiology and Center for Genomic Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA. ²³Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario K1Y4W7, Canada. ²⁴Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada. ²⁵Department ofMedicine, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada. ²⁶Medical Faculty Mannheim, Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Ludolf Krehl Strasse 7-11, Mannheim D-68167, Germany. ²⁷Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria. ²⁸Synlab Academy, Mannheim 68259, Germany. ²⁹The National Heart, Lung, Blood Institute’s Framingham Heart Study, Framingham, Massachusetts 01702, USA. ³⁰National Heart, Lung, and Blood Institute Center for Population Studies, The Framingham Heart Study, Framingham, Massachusetts 01702, USA. ³¹Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ³²Department of Epidemiology, University of Alabama.Birmingham, Birmingham, Alabama 35233, USA. ³³Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. ³⁴School of Medicine, Wake Forest University, Winston.Salem, North Carolina 27106, USA. ³⁵Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ³⁶Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ³⁷Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ³⁸Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota 55455, USA. ³⁹University of MississippiMedical Center, Jackson, Mississippi 39216, USA. ⁴⁰Atherosclerosis Research Unit, Department of Medicine, and Center for Molecular Medicine, Karolinska Institutet, Stockholm 171 77, Sweden. ⁴¹Clinical Trial Service Unit and Epidemiological StudiesUnit, University of Oxford, Oxford OX1 2JD, UK. ⁴²Merck Sharp & Dohme Corporation, Rahway, New Jersey 08889, USA. ⁴³The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK. ⁴⁴Department of Statistics, University of Oxford, Oxford OX1 2JD, UK. ⁴⁵National Heart, Lung, and Blood Institute, Bethesda, Maryland 20824, USA. ⁴⁶Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98195, USA. ⁴⁷Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA. ⁴⁸Section on Cardiology, and Public Health Sciences,Wake Forest School ofMedicine, Winston.Salem, North Carolina 27106, USA. ⁴⁹Jackson Heart Study, University of Mississippi Medical Center, Jackson State University, Jackson, Mississippi 39217, USA. ⁵⁰Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22904, USA. ⁵¹Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. ⁵²Seattle Children’s Hospital, Seattle, Washington 98105, USA. ⁵³Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ⁵⁴Department of Biochemistry, University of Vermont, Burlington, Vermont 05405, USA. ⁵⁵Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ⁵⁶Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ⁵⁷Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ⁵⁸St Luke’s Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri 64111, USA. ⁵⁹Department of Genetics, Washington University in St Louis, Missouri 63130, USA. ⁶⁰Department of Preventive MedicineandInstitute forGeneticMedicine,University ofSouthern CaliforniaKeckSchool of Medicine, Los Angeles, California 90033, USA. ⁶¹Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA. ⁶²Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA. ⁶³Ohio State University, Columbus, Ohio 43210, USA. ⁶⁴Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. ⁶⁵Department of Medicine, School of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁶⁶Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark. ⁶⁷Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Missouri 48109, USA. ⁶⁸Department of Cardiology, Parma Hospital, Parma 43100, Italy. ⁶⁹Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

^*These authors contributed equally to this work.

Abstract
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance^{1, 2}. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families^{3, 4, 5, 6, 7, 8}, whereas common variants at more than 45 loci have been associated with MI risk in the population^{9, 10, 11, 12, 13, 14, 15}. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol¹⁶. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl^-1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase^{15, 17} and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.