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DOI: 10.1038/nature09270
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Biological, clinical and population relevance of 95 loci for blood lipids
Tanya M. Teslovich,Kiran Musunuru,Albert V. Smith,Andrew C. Edmondson,Ioannis M. Stylianou,Masahiro Koseki,James P. Pirruccello,Samuli Ripatti,Daniel I. Chasman,Cristen J. Willer,Christopher T. Johansen,Sigrid W. Fouchier,Aaron Isaacs,Gina M. Peloso,Maja Barbalić,Sally L. Ricketts,Joshua C. Bis,Yurii S. Aulchenko,Guðmar Þorleifsson,Mary F. Feitosa,John C. Chambers,Marju Orho‐Melander,Olle Melander,Toby Johnson,Xiaohui Li,Xiuqing Guo,Mingyao Li,Yoon Shin Cho,Min Jin Go,Young Jin Kim,Jong‐Young Lee,Taesung Park,Kyunga Kim,Xueling Sim,Rick Twee‐Hee Ong,Damien C. Croteau‐Chonka,Leslie A. Lange,Joshua D. Smith,Kijoung Song,Jing Hua Zhao,Xin Yuan,Jian’an Luan,Claudia Lamina,Andreas Ziegler,Weihua Zhang,Robert Y.L. Zee,Alan F. Wright,Jacqueline C. M. Witteman,James F. Wilson,Gonneke Willemsen,H‐Erich Wichmann,John B. Whitfield,Dawn Waterworth,Nicholas J. Wareham,Gérard Waeber,Péter Vollenweider,Benjamin F. Voight,Véronique Vitart,André G. Uitterlinden,Manuela Uda,Jaakko Tuomilehto,John R. Thompson,Toshiko Tanaka,Ida Surakka,Heather M. Stringham,Tim D. Spector,Nicole Soranzo,Johannes H. Smit,Juha Sinisalo,Kaisa Silander,Eric J.G. Sijbrands,Angelo Scuteri,James A. Scott,David Schlessinger,Serena Sanna,Veikko Salomaa,Juha Saharinen,Chiara Sabatti,Aimo Ruokonen,Igor Rudan,Lynda M. Rose,Robert Roberts,Mark J. Rieder,Bruce M. Psaty,Peter P. Pramstaller,Irene Pichler,Markus Perola,Brenda W. J. H. Penninx,Nancy L. Pedersen,Cristian Pattaro,Alex Parker,Guillaume Paré,Ben A. Oostra,Christopher J. O’Donnell,Markku S. Nieminen,Deborah A. Nickerson,Grant W. Montgomery,Thomas Meitinger,Ruth McPherson,Mark I. McCarthy,Wendy L. McArdle,David Masson,Nicholas G. Martin,Fabio Marroni,Massimo Mangino,Patrik K. E. Magnusson,Gavin Lucas,Robert Luben,Ruth J.F. Loos,Marja-Liisa Lokki,Guillaume Lettre,Claudia Langenberg,Lenore J. Launer,Edward G. Lakatta,Reijo Laaksonen,Kirsten Ohm Kyvik,Florian Kronenberg,Inke R. Koenig,Kay‐Tee Khaw,Jaakko Kaprio,Lee M. Kaplan,Åsa Johansson,Marjo‐Riitta Järvelin,A. Cecile J.W. Janssens,Erik Ingelsson,Wilmar Igi,G. Kees Hovingh,Jouke‐Jan Hottenga,Albert Hofman,Andrew A. Hicks,Christian Hengstenberg,Iris M. Heid,Caroline Hayward,Aki S. Havulinna,Nicholas D. Hastie,Tamara B. Harris,Talin Haritunians,Alistair S. Hall,Ulf Gyllensten,Candace Guiducci,Leif Groop,Elena González,Christian Gieger,Nelson B. Freimer,Luigi Ferrucci,Jeanette Erdmann,Paul Elliott,Kenechi G. Ejebe,Angela Doering,Anna F. Dominiczak,Serkalem Demissie,Panos Deloukas,Eco J. C. de Geus,Ulf dé Fairé,Gabriel Crawford,Francis S. Collins,Yii‐Der I. Chen,Mark J. Caulfield,Harry Campbell,Noël P. Burtt,Lori L. Bonnycastle,Dorret I. Boomsma,S. Matthijs Boekholdt,Richard N. Bergman,Inês Barroso,Stefania Bandinelli,Christie M. Ballantyne,Themistocles L. Assimes,Thomas Quertermous,David Altshuler,Mark Seielstad,Tien Yin Wong,E Shyong Tai,Alan B. Feranil,Christopher W. Kuzawa,Linda S. Adair,Herman A. Taylor,Ingrid B. Borecki,Stacey Gabriel,James G. Wilson,Hilma Hólm,Unnur Þorsteinsdóttir,Vilmundur Gudnason,Ronald M. Krauss,Karen L. Mohlke,José M. Ordovás,Patricia B. Munroe,Jaspal S. Kooner,Alan R. Tall,Robert A. Hegele,John J.P. Kastelein,Eric E. Schadt,Jerome I. Rotter,Eric Boerwinkle,David P. Strachan,Vincent Mooser,Kāri Stefánsson,Muredach P. Reilly,Nilesh J. Samani,Heribert Schunkert,L. Adrienne Cupples,Manjinder S. Sandhu,Paul M. Ridker,Daniel J. Rader,Cornelia M. van Duijn,Leena Peltonen,Gonçalo R. Abecasis,Michael Boehnke,Sekar Kathiresan
Single-nucleotide polymorphism
Biology
Genetics
2010
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides 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 plasma 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 (for example, 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 have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma 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. Lipid concentration in the blood is a major risk factor for coronary artery disease, and one that can be targeted for therapeutic intervention. A genome-wide association study (GWAS) in more than 100,000 individuals of European ancestry has been used to identify 95 genetic variants linked to plasma lipids. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and novel loci that contribute to normal variation in lipid traits and to extreme lipid phenotypes. One locus identified in the study as being associated with both plasma low-density lipoprotein cholesterol and coronary artery disease forms the focus of a second paper in this issue. The locus, on chromosome 1p13, is shown to create a binding site for C/EBP transcription factors and to alter SORT1 gene expression in the liver. Modulating Sort1 levels in the mouse liver alters plasma lipoprotein levels, potentially explaining why variation at this locus is associated with heart disease. This finding identifies the sortilin pathway as a possible target for therapeutic intervention and illustrates how GWAS results can be used as a production line for drug targets. Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.
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“Biological, clinical and population relevance of 95 loci for blood lipids” is a paper by Tanya M. Teslovich Kiran Musunuru Albert V. Smith Andrew C. Edmondson Ioannis M. Stylianou Masahiro Koseki James P. Pirruccello Samuli Ripatti Daniel I. Chasman Cristen J. Willer Christopher T. Johansen Sigrid W. Fouchier Aaron Isaacs Gina M. Peloso Maja Barbalić Sally L. Ricketts Joshua C. Bis Yurii S. Aulchenko Guðmar Þorleifsson Mary F. Feitosa John C. Chambers Marju Orho‐Melander Olle Melander Toby Johnson Xiaohui Li Xiuqing Guo Mingyao Li Yoon Shin Cho Min Jin Go Young Jin Kim Jong‐Young Lee Taesung Park Kyunga Kim Xueling Sim Rick Twee‐Hee Ong Damien C. Croteau‐Chonka Leslie A. Lange Joshua D. Smith Kijoung Song Jing Hua Zhao Xin Yuan Jian’an Luan Claudia Lamina Andreas Ziegler Weihua Zhang Robert Y.L. Zee Alan F. Wright Jacqueline C. M. Witteman James F. Wilson Gonneke Willemsen H‐Erich Wichmann John B. Whitfield Dawn Waterworth Nicholas J. Wareham Gérard Waeber Péter Vollenweider Benjamin F. Voight Véronique Vitart André G. Uitterlinden Manuela Uda Jaakko Tuomilehto John R. Thompson Toshiko Tanaka Ida Surakka Heather M. Stringham Tim D. Spector Nicole Soranzo Johannes H. Smit Juha Sinisalo Kaisa Silander Eric J.G. Sijbrands Angelo Scuteri James A. Scott David Schlessinger Serena Sanna Veikko Salomaa Juha Saharinen Chiara Sabatti Aimo Ruokonen Igor Rudan Lynda M. Rose Robert Roberts Mark J. Rieder Bruce M. Psaty Peter P. Pramstaller Irene Pichler Markus Perola Brenda W. J. H. Penninx Nancy L. Pedersen Cristian Pattaro Alex Parker Guillaume Paré Ben A. Oostra Christopher J. O’Donnell Markku S. Nieminen Deborah A. Nickerson Grant W. Montgomery Thomas Meitinger Ruth McPherson Mark I. McCarthy Wendy L. McArdle David Masson Nicholas G. Martin Fabio Marroni Massimo Mangino Patrik K. E. Magnusson Gavin Lucas Robert Luben Ruth J.F. Loos Marja-Liisa Lokki Guillaume Lettre Claudia Langenberg Lenore J. Launer Edward G. Lakatta Reijo Laaksonen Kirsten Ohm Kyvik Florian Kronenberg Inke R. Koenig Kay‐Tee Khaw Jaakko Kaprio Lee M. Kaplan Åsa Johansson Marjo‐Riitta Järvelin A. Cecile J.W. Janssens Erik Ingelsson Wilmar Igi G. Kees Hovingh Jouke‐Jan Hottenga Albert Hofman Andrew A. Hicks Christian Hengstenberg Iris M. Heid Caroline Hayward Aki S. Havulinna Nicholas D. Hastie Tamara B. Harris Talin Haritunians Alistair S. Hall Ulf Gyllensten Candace Guiducci Leif Groop Elena González Christian Gieger Nelson B. Freimer Luigi Ferrucci Jeanette Erdmann Paul Elliott Kenechi G. Ejebe Angela Doering Anna F. Dominiczak Serkalem Demissie Panos Deloukas Eco J. C. de Geus Ulf dé Fairé Gabriel Crawford Francis S. Collins Yii‐Der I. Chen Mark J. Caulfield Harry Campbell Noël P. Burtt Lori L. Bonnycastle Dorret I. Boomsma S. Matthijs Boekholdt Richard N. Bergman Inês Barroso Stefania Bandinelli Christie M. Ballantyne Themistocles L. Assimes Thomas Quertermous David Altshuler Mark Seielstad Tien Yin Wong E Shyong Tai Alan B. Feranil Christopher W. Kuzawa Linda S. Adair Herman A. Taylor Ingrid B. Borecki Stacey Gabriel James G. Wilson Hilma Hólm Unnur Þorsteinsdóttir Vilmundur Gudnason Ronald M. Krauss Karen L. Mohlke José M. Ordovás Patricia B. Munroe Jaspal S. Kooner Alan R. Tall Robert A. Hegele John J.P. Kastelein Eric E. Schadt Jerome I. Rotter Eric Boerwinkle David P. Strachan Vincent Mooser Kāri Stefánsson Muredach P. Reilly Nilesh J. Samani Heribert Schunkert L. Adrienne Cupples Manjinder S. Sandhu Paul M. Ridker Daniel J. Rader Cornelia M. van Duijn Leena Peltonen Gonçalo R. Abecasis Michael Boehnke Sekar Kathiresan published in 2010. It has an Open Access status of “green”. You can read and download a PDF Full Text of this paper here.