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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nature. Author manuscript; available in PMC Feb 15, 2011.
Published in final edited form as:
PMCID: PMC3039276
NIHMSID: NIHMS213289

Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids

Tanya M. Teslovich,1,118 Kiran Musunuru,2,3,4,5,6,118 Albert V. Smith,7,8 Andrew C. Edmondson,9,10 Ioannis M. Stylianou,10 Masahiro Koseki,11 James P. Pirruccello,2,5,6 Samuli Ripatti,12,13 Daniel I. Chasman,4,14 Cristen J. Willer,1 Christopher T. Johansen,15 Sigrid W. Fouchier,16 Aaron Isaacs,17 Gina M. Peloso,18,19 Maja Barbalic,20 Sally L. Ricketts,21 Joshua C. Bis,22 Yurii S. Aulchenko,17 Gudmar Thorleifsson,23 Mary F. Feitosa,24 John Chambers,25 Marju Orho-Melander,26 Olle Melander,26 Toby Johnson,27 Xiaohui Li,28 Xiuqing Guo,28 Mingyao Li,9,10 Yoon Shin Cho,29 Min Jin Go,29 Young Jin Kim,29 Jong-Young Lee,29 Taesung Park,30,31 Kyunga Kim,32 Xueling Sim,33 Rick Twee-Hee Ong,34 Damien C. Croteau-Chonka,35 Leslie A. Lange,35 Joshua D. Smith,36 Kijoung Song,37 Jing Hua Zhao,38 Xin Yuan,37 Jian'an Luan,38 Claudia Lamina,39 CARDIoGRAM Consortium, ENGAGE Consortium, Candidate Gene Association Resource (CARe) Lipids Working Group, Andreas Ziegler,40 Weihua Zhang,25 Robert Y.L. Zee,4,14 Alan F. Wright,41 Jacqueline C.M. Witteman,17,42 James F. Wilson,43 Gonneke Willemsen,44 H-Erich Wichmann,45 John B. Whitfield,46 Dawn M. Waterworth,37 Nicholas J. Wareham,38 Gérard Waeber,47 Peter Vollenweider,47 Benjamin F. Voight,2,5 Veronique Vitart,41 Andre G. Uitterlinden,17,42,48 Manuela Uda,49 Jaakko Tuomilehto,50 John R. Thompson,51 Toshiko Tanaka,52,53 Ida Surakka,12,13 Heather M. Stringham,1 Tim D. Spector,54 Nicole Soranzo,54,55 Johannes H. Smit,56 Juha Sinisalo,57 Kaisa Silander,12,13 Eric J.G. Sijbrands,17,48 Angelo Scuteri,58 James Scott,59 David Schlessinger,60 Serena Sanna,49 Veikko Salomaa,13 Juha Saharinen,61 Chiara Sabatti,62 Aimo Ruokonen,63 Igor Rudan,43 Lynda M. Rose,14 Robert Roberts,64 Mark Rieder,36 Bruce M. Psaty,65 Peter P. Pramstaller,66 Irene Pichler,66 Markus Perola,12,13 Brenda W.J.H. Penninx,56 Nancy L. Pedersen,67 Cristian Pattaro,66 Alex N. Parker,68 Guillaume Pare,69 Ben A. Oostra,70 Christopher J. O'Donnell,4,19 Markku S. Nieminen,57 Deborah A. Nickerson,36 Grant W. Montgomery,46 Thomas Meitinger,71,72 Ruth McPherson,64 Mark I. McCarthy,73,74,75 Wendy McArdle,76 David Masson,11 Nicholas G. Martin,46 Fabio Marroni,77 Massimo Mangino,54 Patrik K.E. Magnusson,67 Gavin Lucas,78 Robert Luben,21 Ruth J. F. Loos,38 Maisa Lokki,38 Guillaume Lettre,79 Claudia Langenberg,38 Lenore J. Launer,80 Edward G. Lakatta,60 Reijo Laaksonen,81 Kirsten O. Kyvik,82 Florian Kronenberg,39 Inke R. König,40 Kay-Tee Khaw,21 Jaakko Kaprio,12,13,83 Lee M. Kaplan,84 Åsa Johansson,85 Marjo-Riitta Jarvelin,86,87 A. Cecile J.W. Janssens,17 Erik Ingelsson,67 Wilmar Igl,85 G. Kees Hovingh,16 Jouke-Jan Hottenga,44 Albert Hofman,17,42 Andrew A. Hicks,66 Christian Hengstenberg,88 Iris M. Heid,45,89 Caroline Hayward,41 Aki S. Havulinna,50,90 Nicholas D. Hastie,41 Tamara B. Harris,80 Talin Haritunians,28 Alistair S. Hall,91 Ulf Gyllensten,85 Candace Guiducci,5 Leif C. Groop,26,92 Elena Gonzalez,5 Christian Gieger,45 Nelson B. Freimer,93 Luigi Ferrucci,94 Jeanette Erdmann,95 Paul Elliott,86,96 Kenechi G. Ejebe,5 Angela Döring,45 Anna F. Dominiczak,97 Serkalem Demissie,18,19 Panagiotis Deloukas,55 Eco J.C. de Geus,44 Ulf de Faire,98 Gabriel Crawford,5 Francis S. Collins,99 Yii-der I. Chen,28 Mark J. Caulfield,27 Harry Campbell,43 Noel P. Burtt,5 Lori L. Bonnycastle,99 Dorret I. Boomsma,44 S. Matthijs Boekholdt,100 Richard N. Bergman,101 Inês Barroso,55 Stefania Bandinelli,102 Christie M. Ballantyne,103 Themistocles L. Assimes,104 Thomas Quertermous,104 David Altshuler,2,4,5 Mark Seielstad,34 Tien Y. Wong,105 E-Shyong Tai,106 Alan B. Feranil,107 Christopher W. Kuzawa,108 Linda S. Adair,109 Herman A. Taylor, Jr.,110 Ingrid B. Borecki,24 Stacey B. Gabriel,5 James G. Wilson,110 Kari Stefansson,23 Unnur Thorsteinsdottir,23 Vilmundur Gudnason,7,111 Ronald M. Krauss,112 Karen L. Mohlke,35 Jose M. Ordovas,113 Patricia B. Munroe,114 Jaspal S. Kooner,59 Alan R. Tall,11 Robert A. Hegele,15 John J.P. Kastelein,16 Eric E. Schadt,115 Jerome I. Rotter,28 Eric Boerwinkle,20 David P. Strachan,116 Vincent Mooser,37 Hilma Holm,23 Muredach P. Reilly,9,10 Nilesh J Samani,61,117 Heribert Schunkert,95 L. Adrienne Cupples,18,19,119 Manjinder S. Sandhu,21,38,55,119 Paul M Ridker,4,14,119 Daniel J. Rader,9,10,119 Cornelia M. van Duijn,17,42,119 Leena Peltonen,5,12,13,55,119 Gonçalo R. Abecasis,1,119 Michael Boehnke,1,119 and Sekar Kathiresan2,3,4,5,119

Abstract

Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with serum lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (e.g., CYP7A1, NPC1L1, and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and impact lipid traits in three non-European populations (East Asians, South Asians, and African Americans). Our results identify several novel loci associated with serum lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B, and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

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