Chen Yao1, Brian H Chen1, Roby Joehanes1, Burcak Otlu1, Xiaoling Zhang1, Chunyu Liu1, Tianxiao Huan1, Oznur Tastan1, L Adrienne Cupples1, James B Meigs1, Caroline S Fox1, Jane E Freedman1, Paul Courchesne1, Christopher J O'Donnell1, Peter J Munson1, Sunduz Keles1, Daniel Levy2. 1. From the National Heart, Lung, and Blood Institute's Framingham Heart Study, National Institutes of Health, Bethesda, MD (C.Y., B.H.C., R.J., X.Z., C.L., T.H., L.A.C., C.S.F., P.C., C.J.O'D., D.L.); Population Sciences Branch, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD (C.Y., B.H.C., R.J., X.Z., C.L., T.H., P.C., D.L.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M.); Department of Computer Engineering, Middle East Technical University, Ankara, Turkey (B.O.); Department of Computer Engineering, Bilkent University, Ankara, Turkey (O.T.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (L.A.C.); Harvard Medical School, Boston, MA (J.B.M.); Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (C.S.F.); Department of Medicine, University of Massachusetts Medical School, Worchester (J.E.F.); Division of Cardiology, Massachusetts General Hospital, Boston, MA (C.J.O'D.); and Departments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin-Madison (S.K.). 2. From the National Heart, Lung, and Blood Institute's Framingham Heart Study, National Institutes of Health, Bethesda, MD (C.Y., B.H.C., R.J., X.Z., C.L., T.H., L.A.C., C.S.F., P.C., C.J.O'D., D.L.); Population Sciences Branch, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD (C.Y., B.H.C., R.J., X.Z., C.L., T.H., P.C., D.L.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M.); Department of Computer Engineering, Middle East Technical University, Ankara, Turkey (B.O.); Department of Computer Engineering, Bilkent University, Ankara, Turkey (O.T.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (L.A.C.); Harvard Medical School, Boston, MA (J.B.M.); Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (C.S.F.); Department of Medicine, University of Massachusetts Medical School, Worchester (J.E.F.); Division of Cardiology, Massachusetts General Hospital, Boston, MA (C.J.O'D.); and Departments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin-Madison (S.K.). LevyD@nih.gov.
Abstract
BACKGROUND: Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. METHODS AND RESULTS: We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. CONCLUSIONS: Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD.
BACKGROUND:Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. METHODS AND RESULTS: We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. CONCLUSIONS: Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD.
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Authors: Georg B Ehret; Patricia B Munroe; Kenneth M Rice; Murielle Bochud; Andrew D Johnson; Daniel I Chasman; Albert V Smith; Martin D Tobin; Germaine C Verwoert; Shih-Jen Hwang; Vasyl Pihur; Peter Vollenweider; Paul F O'Reilly; Najaf Amin; Jennifer L Bragg-Gresham; Alexander Teumer; Nicole L Glazer; Lenore Launer; Jing Hua Zhao; Yurii Aulchenko; Simon Heath; Siim Sõber; Afshin Parsa; Jian'an Luan; Pankaj Arora; Abbas Dehghan; Feng Zhang; Gavin Lucas; Andrew A Hicks; Anne U Jackson; John F Peden; Toshiko Tanaka; Sarah H Wild; Igor Rudan; Wilmar Igl; Yuri Milaneschi; Alex N Parker; Cristiano Fava; John C Chambers; Ervin R Fox; Meena Kumari; Min Jin Go; Pim van der Harst; Wen Hong Linda Kao; Marketa Sjögren; D G Vinay; Myriam Alexander; Yasuharu Tabara; Sue Shaw-Hawkins; Peter H Whincup; Yongmei Liu; Gang Shi; Johanna Kuusisto; Bamidele Tayo; Mark Seielstad; Xueling Sim; Khanh-Dung Hoang Nguyen; Terho Lehtimäki; Giuseppe Matullo; Ying Wu; Tom R Gaunt; N Charlotte Onland-Moret; Matthew N Cooper; Carl G P Platou; Elin Org; Rebecca Hardy; Santosh Dahgam; Jutta Palmen; Veronique Vitart; Peter S Braund; Tatiana Kuznetsova; Cuno S P M Uiterwaal; Adebowale Adeyemo; Walter Palmas; Harry Campbell; Barbara Ludwig; Maciej Tomaszewski; Ioanna Tzoulaki; Nicholette D Palmer; Thor Aspelund; Melissa Garcia; Yen-Pei C Chang; Jeffrey R O'Connell; Nanette I Steinle; Diederick E Grobbee; Dan E Arking; Sharon L Kardia; Alanna C Morrison; Dena Hernandez; Samer Najjar; Wendy L McArdle; David Hadley; Morris J Brown; John M Connell; Aroon D Hingorani; Ian N M Day; Debbie A Lawlor; John P Beilby; Robert W Lawrence; Robert Clarke; Jemma C Hopewell; Halit Ongen; Albert W Dreisbach; Yali Li; J Hunter Young; Joshua C Bis; Mika Kähönen; Jorma Viikari; Linda S Adair; Nanette R Lee; Ming-Huei Chen; Matthias Olden; Cristian Pattaro; Judith A Hoffman Bolton; Anna Köttgen; Sven Bergmann; Vincent Mooser; Nish Chaturvedi; Timothy M Frayling; Muhammad Islam; Tazeen H Jafar; Jeanette Erdmann; Smita R Kulkarni; Stefan R Bornstein; Jürgen Grässler; Leif Groop; Benjamin F Voight; Johannes Kettunen; Philip Howard; Andrew Taylor; Simonetta Guarrera; Fulvio Ricceri; Valur Emilsson; Andrew Plump; Inês Barroso; Kay-Tee Khaw; Alan B Weder; Steven C Hunt; Yan V Sun; Richard N Bergman; Francis S Collins; Lori L Bonnycastle; Laura J Scott; Heather M Stringham; Leena Peltonen; Markus Perola; Erkki Vartiainen; Stefan-Martin Brand; Jan A Staessen; Thomas J Wang; Paul R Burton; Maria Soler Artigas; Yanbin Dong; Harold Snieder; Xiaoling Wang; Haidong Zhu; Kurt K Lohman; Megan E Rudock; Susan R Heckbert; Nicholas L Smith; Kerri L Wiggins; Ayo Doumatey; Daniel Shriner; Gudrun Veldre; Margus Viigimaa; Sanjay Kinra; Dorairaj Prabhakaran; Vikal Tripathy; Carl D Langefeld; Annika Rosengren; Dag S Thelle; Anna Maria Corsi; Andrew Singleton; Terrence Forrester; Gina Hilton; Colin A McKenzie; Tunde Salako; Naoharu Iwai; Yoshikuni Kita; Toshio Ogihara; Takayoshi Ohkubo; Tomonori Okamura; Hirotsugu Ueshima; Satoshi Umemura; Susana Eyheramendy; Thomas Meitinger; H-Erich Wichmann; Yoon Shin Cho; Hyung-Lae Kim; Jong-Young Lee; James Scott; Joban S Sehmi; Weihua Zhang; Bo Hedblad; Peter Nilsson; George Davey Smith; Andrew Wong; Narisu Narisu; Alena Stančáková; Leslie J Raffel; Jie Yao; Sekar Kathiresan; Christopher J O'Donnell; Stephen M Schwartz; M Arfan Ikram; W T Longstreth; Thomas H Mosley; Sudha Seshadri; Nick R G Shrine; Louise V Wain; Mario A Morken; Amy J Swift; Jaana Laitinen; Inga Prokopenko; Paavo Zitting; Jackie A Cooper; Steve E Humphries; John Danesh; Asif Rasheed; Anuj Goel; Anders Hamsten; Hugh Watkins; Stephan J L Bakker; Wiek H van Gilst; Charles S Janipalli; K Radha Mani; Chittaranjan S Yajnik; Albert Hofman; Francesco U S Mattace-Raso; Ben A Oostra; Ayse Demirkan; Aaron Isaacs; Fernando Rivadeneira; Edward G Lakatta; Marco Orru; Angelo Scuteri; Mika Ala-Korpela; Antti J Kangas; Leo-Pekka Lyytikäinen; Pasi Soininen; Taru Tukiainen; Peter Würtz; Rick Twee-Hee Ong; Marcus Dörr; Heyo K Kroemer; Uwe Völker; Henry Völzke; Pilar Galan; Serge Hercberg; Mark Lathrop; Diana Zelenika; Panos Deloukas; Massimo Mangino; Tim D Spector; Guangju Zhai; James F Meschia; Michael A Nalls; Pankaj Sharma; Janos Terzic; M V Kranthi Kumar; Matthew Denniff; Ewa Zukowska-Szczechowska; Lynne E Wagenknecht; F Gerald R Fowkes; Fadi J Charchar; Peter E H Schwarz; Caroline Hayward; Xiuqing Guo; Charles Rotimi; Michiel L Bots; Eva Brand; Nilesh J Samani; Ozren Polasek; Philippa J Talmud; Fredrik Nyberg; Diana Kuh; Maris Laan; Kristian Hveem; Lyle J Palmer; Yvonne T van der Schouw; Juan P Casas; Karen L Mohlke; Paolo Vineis; Olli Raitakari; Santhi K Ganesh; Tien Y Wong; E Shyong Tai; Richard S Cooper; Markku Laakso; Dabeeru C Rao; Tamara B Harris; Richard W Morris; Anna F Dominiczak; Mika Kivimaki; Michael G Marmot; Tetsuro Miki; Danish Saleheen; Giriraj R Chandak; Josef Coresh; Gerjan Navis; Veikko Salomaa; Bok-Ghee Han; Xiaofeng Zhu; Jaspal S Kooner; Olle Melander; Paul M Ridker; Stefania Bandinelli; Ulf B Gyllensten; Alan F Wright; James F Wilson; Luigi Ferrucci; Martin Farrall; Jaakko Tuomilehto; Peter P Pramstaller; Roberto Elosua; Nicole Soranzo; Eric J G Sijbrands; David Altshuler; Ruth J F Loos; Alan R Shuldiner; Christian Gieger; Pierre Meneton; Andre G Uitterlinden; Nicholas J Wareham; Vilmundur Gudnason; Jerome I Rotter; Rainer Rettig; Manuela Uda; David P Strachan; Jacqueline C M Witteman; Anna-Liisa Hartikainen; Jacques S Beckmann; Eric Boerwinkle; Ramachandran S Vasan; Michael Boehnke; Martin G Larson; Marjo-Riitta Järvelin; Bruce M Psaty; Gonçalo R Abecasis; Aravinda Chakravarti; Paul Elliott; Cornelia M van Duijn; Christopher Newton-Cheh; Daniel Levy; Mark J Caulfield; Toby Johnson Journal: Nature Date: 2011-09-11 Impact factor: 49.962
Authors: Marc Jan Bonder; René Luijk; Daria V Zhernakova; Matthijs Moed; Patrick Deelen; Martijn Vermaat; Maarten van Iterson; Freerk van Dijk; Michiel van Galen; Jan Bot; Roderick C Slieker; P Mila Jhamai; Michael Verbiest; H Eka D Suchiman; Marijn Verkerk; Ruud van der Breggen; Jeroen van Rooij; Nico Lakenberg; Wibowo Arindrarto; Szymon M Kielbasa; Iris Jonkers; Peter van 't Hof; Irene Nooren; Marian Beekman; Joris Deelen; Diana van Heemst; Alexandra Zhernakova; Ettje F Tigchelaar; Morris A Swertz; Albert Hofman; André G Uitterlinden; René Pool; Jenny van Dongen; Jouke J Hottenga; Coen D A Stehouwer; Carla J H van der Kallen; Casper G Schalkwijk; Leonard H van den Berg; Erik W van Zwet; Hailiang Mei; Yang Li; Mathieu Lemire; Thomas J Hudson; P Eline Slagboom; Cisca Wijmenga; Jan H Veldink; Marleen M J van Greevenbroek; Cornelia M van Duijn; Dorret I Boomsma; Aaron Isaacs; Rick Jansen; Joyce B J van Meurs; Peter A C 't Hoen; Lude Franke; Bastiaan T Heijmans Journal: Nat Genet Date: 2016-12-05 Impact factor: 38.330
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