Hayato Tada1, Hong-Hee Won1, Olle Melander1, Jian Yang1, Gina M Peloso1, Sekar Kathiresan2. 1. From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.). 2. From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.). sekar@broadinstitute.org.
Abstract
BACKGROUND: Plasma lipid levels as well as coronary artery disease (CAD) have been shown to be highly heritable with estimates ranging from 40% to 60%. However, top variants detected by large-scale genome-wide association studies explain only a fraction of the total variance in plasma lipid phenotypes and CAD. METHODS AND RESULTS: We performed a conditional and joint association analysis using summary-level statistics from 2 large genome-wide association meta-analyses: the Global Lipids Genetics Consortium (GLGC) study, and the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study. There were 100 184 individuals from 46 GLGC studies for plasma lipids, and 22 233 cases and 64 762 controls from 14 studies for CAD. We detected several loci where multiple independent single-nucleotide polymorphisms were associated with lipid traits within a locus (12 out of 33 loci for high-density lipoprotein cholesterol, 10 of 35 loci for low-density lipoprotein cholesterol, 13 of 44 loci for total cholesterol, and 8 of 28 loci for triglycerides), reaching genome-wide significance (P<5×10(-8)), nearly doubling the heritability explained by genome-wide association studies (from 3.6 to 7.6% for high-density lipoprotein cholesterol, from 5.0 to 8.8% for low-density lipoprotein cholesterol, from 5.5 to 8.8% for total cholesterol, and from 5.7 to 8.5% for triglycerides). Multiple single-nucleotide polymorphisms were also associated with CAD (3 of 15 loci; an increase from 9.6% to 11.4% of heritability explained). CONCLUSIONS: These results demonstrate that a portion of the missing heritability for lipid traits and CAD can be explained by multiple variants at each locus.
BACKGROUND: Plasma lipid levels as well as coronary artery disease (CAD) have been shown to be highly heritable with estimates ranging from 40% to 60%. However, top variants detected by large-scale genome-wide association studies explain only a fraction of the total variance in plasma lipid phenotypes and CAD. METHODS AND RESULTS: We performed a conditional and joint association analysis using summary-level statistics from 2 large genome-wide association meta-analyses: the Global Lipids Genetics Consortium (GLGC) study, and the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study. There were 100 184 individuals from 46 GLGC studies for plasma lipids, and 22 233 cases and 64 762 controls from 14 studies for CAD. We detected several loci where multiple independent single-nucleotide polymorphisms were associated with lipid traits within a locus (12 out of 33 loci for high-density lipoprotein cholesterol, 10 of 35 loci for low-density lipoprotein cholesterol, 13 of 44 loci for total cholesterol, and 8 of 28 loci for triglycerides), reaching genome-wide significance (P<5×10(-8)), nearly doubling the heritability explained by genome-wide association studies (from 3.6 to 7.6% for high-density lipoprotein cholesterol, from 5.0 to 8.8% for low-density lipoprotein cholesterol, from 5.5 to 8.8% for total cholesterol, and from 5.7 to 8.5% for triglycerides). Multiple single-nucleotide polymorphisms were also associated with CAD (3 of 15 loci; an increase from 9.6% to 11.4% of heritability explained). CONCLUSIONS: These results demonstrate that a portion of the missing heritability for lipid traits and CAD can be explained by multiple variants at each locus.
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Jian Yang; Beben Benyamin; Brian P McEvoy; Scott Gordon; Anjali K Henders; Dale R Nyholt; Pamela A Madden; Andrew C Heath; Nicholas G Martin; Grant W Montgomery; Michael E Goddard; Peter M Visscher Journal: Nat Genet Date: 2010-06-20 Impact factor: 38.330
Authors: Panos Deloukas; Stavroula Kanoni; Christina Willenborg; Martin Farrall; Themistocles L Assimes; John R Thompson; Erik Ingelsson; Danish Saleheen; Jeanette Erdmann; Benjamin A Goldstein; Kathleen Stirrups; Inke R König; Jean-Baptiste Cazier; Asa Johansson; Alistair S Hall; Jong-Young Lee; Cristen J Willer; John C Chambers; Tõnu Esko; Lasse Folkersen; Anuj Goel; Elin Grundberg; Aki S Havulinna; Weang K Ho; Jemma C Hopewell; Niclas Eriksson; Marcus E Kleber; Kati Kristiansson; Per Lundmark; Leo-Pekka Lyytikäinen; Suzanne Rafelt; Dmitry Shungin; Rona J Strawbridge; Gudmar Thorleifsson; Emmi Tikkanen; Natalie Van Zuydam; Benjamin F Voight; Lindsay L Waite; Weihua Zhang; Andreas Ziegler; Devin Absher; David Altshuler; Anthony J Balmforth; Inês Barroso; Peter S Braund; Christof Burgdorf; Simone Claudi-Boehm; David Cox; Maria Dimitriou; Ron Do; Alex S F Doney; NourEddine El Mokhtari; Per Eriksson; Krista Fischer; Pierre Fontanillas; Anders Franco-Cereceda; Bruna Gigante; Leif Groop; Stefan Gustafsson; Jörg Hager; Göran Hallmans; Bok-Ghee Han; Sarah E Hunt; Hyun M Kang; Thomas Illig; Thorsten Kessler; Joshua W Knowles; Genovefa Kolovou; Johanna Kuusisto; Claudia Langenberg; Cordelia Langford; Karin Leander; Marja-Liisa Lokki; Anders Lundmark; Mark I McCarthy; Christa Meisinger; Olle Melander; Evelin Mihailov; Seraya Maouche; Andrew D Morris; Martina Müller-Nurasyid; Kjell Nikus; John F Peden; N William Rayner; Asif Rasheed; Silke Rosinger; Diana Rubin; Moritz P Rumpf; Arne Schäfer; Mohan Sivananthan; Ci Song; Alexandre F R Stewart; Sian-Tsung Tan; Gudmundur Thorgeirsson; C Ellen van der Schoot; Peter J Wagner; George A Wells; Philipp S Wild; Tsun-Po Yang; Philippe Amouyel; Dominique Arveiler; Hanneke Basart; Michael Boehnke; Eric Boerwinkle; Paolo Brambilla; Francois Cambien; Adrienne L Cupples; Ulf de Faire; Abbas Dehghan; Patrick Diemert; Stephen E Epstein; Alun Evans; Marco M Ferrario; Jean Ferrières; Dominique Gauguier; Alan S Go; Alison H Goodall; Villi Gudnason; Stanley L Hazen; Hilma Holm; Carlos Iribarren; Yangsoo Jang; Mika Kähönen; Frank Kee; Hyo-Soo Kim; Norman Klopp; Wolfgang Koenig; Wolfgang Kratzer; Kari Kuulasmaa; Markku Laakso; Reijo Laaksonen; Ji-Young Lee; Lars Lind; Willem H Ouwehand; Sarah Parish; Jeong E Park; Nancy L Pedersen; Annette Peters; Thomas Quertermous; Daniel J Rader; Veikko Salomaa; Eric Schadt; Svati H Shah; Juha Sinisalo; Klaus Stark; Kari Stefansson; David-Alexandre Trégouët; Jarmo Virtamo; Lars Wallentin; Nicholas Wareham; Martina E Zimmermann; Markku S Nieminen; Christian Hengstenberg; Manjinder S Sandhu; Tomi Pastinen; Ann-Christine Syvänen; G Kees Hovingh; George Dedoussis; Paul W Franks; Terho Lehtimäki; Andres Metspalu; Pierre A Zalloua; Agneta Siegbahn; Stefan Schreiber; Samuli Ripatti; Stefan S Blankenberg; Markus Perola; Robert Clarke; Bernhard O Boehm; Christopher O'Donnell; Muredach P Reilly; Winfried März; Rory Collins; Sekar Kathiresan; Anders Hamsten; Jaspal S Kooner; Unnur Thorsteinsdottir; John Danesh; Colin N A Palmer; Robert Roberts; Hugh Watkins; Heribert Schunkert; Nilesh J Samani Journal: Nat Genet Date: 2012-12-02 Impact factor: 38.330
Authors: Teri A Manolio; Francis S Collins; Nancy J Cox; David B Goldstein; Lucia A Hindorff; David J Hunter; Mark I McCarthy; Erin M Ramos; Lon R Cardon; Aravinda Chakravarti; Judy H Cho; Alan E Guttmacher; Augustine Kong; Leonid Kruglyak; Elaine Mardis; Charles N Rotimi; Montgomery Slatkin; David Valle; Alice S Whittemore; Michael Boehnke; Andrew G Clark; Evan E Eichler; Greg Gibson; Jonathan L Haines; Trudy F C Mackay; Steven A McCarroll; Peter M Visscher Journal: Nature Date: 2009-10-08 Impact factor: 49.962
Authors: Jian Yang; Teresa Ferreira; Andrew P Morris; Sarah E Medland; Pamela A F Madden; Andrew C Heath; Nicholas G Martin; Grant W Montgomery; Michael N Weedon; Ruth J Loos; Timothy M Frayling; Mark I McCarthy; Joel N Hirschhorn; Michael E Goddard; Peter M Visscher Journal: Nat Genet Date: 2012-03-18 Impact factor: 38.330
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Authors: Stavroula Kanoni; Nicholas G D Masca; Kathleen E Stirrups; Tibor V Varga; Helen R Warren; Robert A Scott; Lorraine Southam; Weihua Zhang; Hanieh Yaghootkar; Martina Müller-Nurasyid; Alexessander Couto Alves; Rona J Strawbridge; Lazaros Lataniotis; Nikman An Hashim; Céline Besse; Anne Boland; Peter S Braund; John M Connell; Anna Dominiczak; Aliki-Eleni Farmaki; Stephen Franks; Harald Grallert; Jan-Håkan Jansson; Maria Karaleftheri; Sirkka Keinänen-Kiukaanniemi; Angela Matchan; Dorota Pasko; Annette Peters; Neil Poulter; Nigel W Rayner; Frida Renström; Olov Rolandsson; Maria Sabater-Lleal; Bengt Sennblad; Peter Sever; Denis Shields; Angela Silveira; Alice V Stanton; Konstantin Strauch; Maciej Tomaszewski; Emmanouil Tsafantakis; Melanie Waldenberger; Alexandra I F Blakemore; George Dedoussis; Stefan A Escher; Jaspal S Kooner; Mark I McCarthy; Colin N A Palmer; Anders Hamsten; Mark J Caulfield; Timothy M Frayling; Martin D Tobin; Marjo-Riitta Jarvelin; Eleftheria Zeggini; Christian Gieger; John C Chambers; Nick J Wareham; Patricia B Munroe; Paul W Franks; Nilesh J Samani; Panos Deloukas Journal: Hum Mol Genet Date: 2016-07-27 Impact factor: 6.150
Authors: Justin R Ryder; Nathan D Pankratz; Donald R Dengel; James S Pankow; David R Jacobs; Alan R Sinaiko; Vasu Gooty; Julia Steinberger Journal: J Am Heart Assoc Date: 2017-02-02 Impact factor: 5.501
Authors: María Soler Artigas; Louise V Wain; Suzanne Miller; Abdul Kader Kheirallah; Jennifer E Huffman; Ioanna Ntalla; Nick Shrine; Ma'en Obeidat; Holly Trochet; Wendy L McArdle; Alexessander Couto Alves; Jennie Hui; Jing Hua Zhao; Peter K Joshi; Alexander Teumer; Eva Albrecht; Medea Imboden; Rajesh Rawal; Lorna M Lopez; Jonathan Marten; Stefan Enroth; Ida Surakka; Ozren Polasek; Leo-Pekka Lyytikäinen; Raquel Granell; Pirro G Hysi; Claudia Flexeder; Anubha Mahajan; John Beilby; Yohan Bossé; Corry-Anke Brandsma; Harry Campbell; Christian Gieger; Sven Gläser; Juan R González; Harald Grallert; Chris J Hammond; Sarah E Harris; Anna-Liisa Hartikainen; Markku Heliövaara; John Henderson; Lynne Hocking; Momoko Horikoshi; Nina Hutri-Kähönen; Erik Ingelsson; Åsa Johansson; John P Kemp; Ivana Kolcic; Ashish Kumar; Lars Lind; Erik Melén; Arthur W Musk; Pau Navarro; David C Nickle; Sandosh Padmanabhan; Olli T Raitakari; Janina S Ried; Samuli Ripatti; Holger Schulz; Robert A Scott; Don D Sin; John M Starr; Ana Viñuela; Henry Völzke; Sarah H Wild; Alan F Wright; Tatijana Zemunik; Deborah L Jarvis; Tim D Spector; David M Evans; Terho Lehtimäki; Veronique Vitart; Mika Kähönen; Ulf Gyllensten; Igor Rudan; Ian J Deary; Stefan Karrasch; Nicole M Probst-Hensch; Joachim Heinrich; Beate Stubbe; James F Wilson; Nicholas J Wareham; Alan L James; Andrew P Morris; Marjo-Riitta Jarvelin; Caroline Hayward; Ian Sayers; David P Strachan; Ian P Hall; Martin D Tobin Journal: Nat Commun Date: 2015-12-04 Impact factor: 14.919
Authors: Christopher D Anderson; Guido J Falcone; Chia-Ling Phuah; Farid Radmanesh; H Bart Brouwers; Thomas W K Battey; Alessandro Biffi; Gina M Peloso; Dajiang J Liu; Alison M Ayres; Joshua N Goldstein; Anand Viswanathan; Steven M Greenberg; Magdy Selim; James F Meschia; Devin L Brown; Bradford B Worrall; Scott L Silliman; David L Tirschwell; Matthew L Flaherty; Peter Kraft; Jeremiasz M Jagiella; Helena Schmidt; Björn M Hansen; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Koen M van Nieuwenhuizen; Catharina J M Klijn; Kristiina Rannikmae; Neshika Samarasekera; Rustam Al-Shahi Salman; Catherine L Sudlow; Ian J Deary; Andrea Morotti; Alessandro Pezzini; Joanna Pera; Andrzej Urbanik; Alexander Pichler; Christian Enzinger; Bo Norrving; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Jaume Roquer; Arne Lindgren; Agnieszka Slowik; Reinhold Schmidt; Chelsea S Kidwell; Steven J Kittner; Salina P Waddy; Carl D Langefeld; Goncalo Abecasis; Cristen J Willer; Sekar Kathiresan; Daniel Woo; Jonathan Rosand Journal: Ann Neurol Date: 2016-10-19 Impact factor: 10.422