2008 Nature Publishing Group http www nature com naturegenetics ARTICLES Newly identified loci that influence lipid concentrations and risk of coronary artery disease Cristen J Willer1 18 Serena Sanna1 2 18 Anne U Jackson1 Angelo Scuteri3 4 Lori L Bonnycastle5 Robert Clarke6 Simon C Heath7 Nicholas J Timpson8 Samer S Najjar3 Heather M Stringham1 James Strait3 William L Duren1 Andrea Maschio2 Fabio Busonero2 Antonella Mulas2 Giuseppe Albai2 Amy J Swift5 Mario A Morken5 Narisu Narisu5 Derrick Bennett6 Sarah Parish6 Haiqing Shen9 Pilar Galan10 Pierre Meneton11 Serge Hercberg11 Diana Zelenika7 Wei Min Chen1 Yun Li1 Laura J Scott1 Paul A Scheet1 Jouko Sundvall12 Richard M Watanabe13 14 Ramaiah Nagaraja3 Shah Ebrahim15 Debbie A Lawlor8 Yoav Ben Shlomo8 George Davey Smith8 Alan R Shuldiner9 Rory Collins6 Richard N Bergman13 Manuela Uda2 Jaakko Tuomilehto16 Antonio Cao2 Francis S Collins5 Edward Lakatta3 G Mark Lathrop7 Michael Boehnke1 David Schlessinger3 Karen L Mohlke17 Gonc alo R Abecasis1 To identify genetic variants influencing plasma lipid concentrations we first used genotype imputation and meta analysis to combine three genome wide scans totaling 8 816 individuals and comprising 6 068 individuals specific to our study 1 874 individuals from the FUSION study of type 2 diabetes and 4 184 individuals from the SardiNIA study of aging associated variables and 2 758 individuals from the Diabetes Genetics Initiative reported in a companion study in this issue We subsequently examined promising signals in 11 569 additional individuals Overall we identify strongly associated variants in eleven loci previously implicated in lipid metabolism ABCA1 the APOA5 APOA4 APOC3 APOA1 and APOE APOC clusters APOB CETP GCKR LDLR LPL LIPC LIPG and PCSK9 and also in several newly identified loci near MVK MMAB and GALNT2 with variants primarily associated with high density lipoprotein HDL cholesterol near SORT1 with variants primarily associated with low density lipoprotein LDL cholesterol near TRIB1 MLXIPL and ANGPTL3 with variants primarily associated with triglycerides and a locus encompassing several genes near NCAN with variants strongly associated with both triglycerides and LDL cholesterol Notably the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls Coronary artery disease CAD and stroke are the leading causes of morbidity mortality and disability in industrialized countries and the prevalence of these diseases is increasing rapidly in developing countries1 A main underlying pathology is atherosclerosis a process of cumulative deposition of LDL cholesterol in the arteries supplying blood to the heart and brain that eventually leads to impaired or absent blood supply and myocardial infarction or stroke1 Consistent and compelling evidence has demonstrated association between lipoprotein associated lipid concentrations and cardiovascular disease incidence worldwide2 4 Whereas high concentrations of LDL 1Center for Statistical Genetics Department of Biostatistics University of Michigan 1420 Washington Heights Ann Arbor Michigan 48109 USA 2Istituto di Neurogenetica e Neurofarmacologia INN Consiglio Nazionale delle Ricerche c o Cittadella Universitaria di Monserrato Monserrato Cagliari Italy 09042 3Gerontology Research Center National Institute on Aging 5600 Nathan Shock Drive Baltimore Maryland 21224 USA 4Unita Operativa Geriatria Istituto per la Patologia Endocrina e Metabolica Rome Italy 5Genome Technology Branch National Human Genome Research Institute Bethesda Maryland 20892 USA 6Clinical Trial Service Unit University of Oxford Richard Doll Building Old Road Campus Roosevelt Drive Oxford OX3 7LF UK 7Centre National de Ge notypage Institut Ge nomique Commissariat a l E nergie Atomique 2 rue Gaston Cre mieux CP 5721 91057 Evry Cedex France 8Department of Social Medicine University of Bristol Canynge Hall Whiteladies Road Bristol BS8 2PR UK 9Division of Endocrinology Diabetes and Nutrition University of Maryland School of Medicine Baltimore Maryland 21201 USA 10U872 Institut National de la Sante et de la Recherche Me dicale INSERM and De partement de Sante Publique et d Informatique Me dicale Faculte de Me decine Rene Descartes 15 rue de l Ecole de Me decine 75270 Paris France 11U557 INSERM U1125 Institut National de la Recherche Agronomique INRA Cnam Paris 13 University Centre de Recherche en Nutrition Humaine CRNH IdF 74 rue Marcel Cachin 93017 Bobigny Cedex France 12Laboratory of Analytical Biochemistry Department of Health and Functional Capacity National Public Health Institute 00300 Helsinki Finland 13Department of Physiology and Biophysics Keck School of Medicine University of Southern California Los Angeles California 90033 USA 14Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles California 90089 USA 15Department of Epidemiology and Population Health London School of Hygiene Tropical Medicine Keppel St London WC1E 7HT UK 16Diabetes Unit Department of Health Promotion and Chronic Disease Prevention National Public Health Institute 00300 Helsinki Finland and Department of Public Health University of Helsinki 00014 Helsinki Finland 17Department of Genetics University of North Carolina Chapel Hill North Carolina 27599 USA 18These authors contributed equally to the work Correspondence should be addressed to G R A goncalo umich edu or K L M mohlke med unc edu Received 3 October 2007 accepted 7 December 2007 published online 13 January 2008 doi 10 1038 ng 76 NATURE GENETICS VOLUME 40 NUMBER 2 FEBRUARY 2008 161 2008 Nature Publishing Group http www nature com naturegenetics ARTICLES cholesterol are associated with increased risk of CAD high concentrations of HDL cholesterol are associated with decreased risk of CAD Specifically it has been estimated that each 1 decrease in LDL cholesterol concentrations reduces the risk of coronary heart disease by B1 ref 5 and each 1 increase in HDL cholesterol concentrations reduces the risk of coronary heart disease by B2 ref 6 A recent meta analysis of data on 150 000 individuals including 3 000 with CAD related deaths shows that the two factors are independently associated with CAD risk7 There is evidence that a high concentration of triglycerides is an additional independent risk factor for cardiovascular disease8 9 although whether this association is causal is still