Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
Alvaro Barbeira(University of Chicago), Scott Dickinson(University of Chicago), Rodrigo Bonazzola(University of Chicago), Jiamao Zheng(University of Chicago), Heather E. Wheeler(Loyola University Chicago), Jason Torres(University of Chicago), Eric S. Torstenson(Vanderbilt University Medical Center), Kaanan P. Shah(University of Chicago), Tzintzuni Garcia(University of Chicago), Todd L. Edwards(Vanderbilt University Medical Center), Eli A. Stahl(Icahn School of Medicine at Mount Sinai), Laura M. Huckins(Icahn School of Medicine at Mount Sinai), François Aguet(Broad Institute), Kristin Ardlie(Broad Institute), Beryl B. Cummings(Broad Institute), Ellen Gelfand(Broad Institute), Gad Getz(Broad Institute), Kane Hadley(Broad Institute), Robert E. Handsaker(Broad Institute), Katherine Huang(Broad Institute), Seva Kashin(Broad Institute), Konrad J. Karczewski(Broad Institute), Monkol Lek(Broad Institute), Xiao Li(Broad Institute), Daniel G. MacArthur(Broad Institute), Jared L. Nedzel(Broad Institute), Duyen T. Nguyen(Broad Institute), Michael S. Noble(Broad Institute), Ayellet V. Segrè(Broad Institute), Casandra A. Trowbridge(Broad Institute), Taru Tukiainen(Broad Institute), Statistical Methods groups—Analysis Working Group(Stanford University), Nathan S. Abell(Stanford University), Brunilda Balliu(Ben-Gurion University of the Negev), Ruth Barshir(Ben-Gurion University of the Negev), Omer Basha(Johns Hopkins University), Alexis Battle(Barcelona Institute of Science and Technology), Gireesh K. Bogu(University of Geneva), Andrew Brown(University of Pennsylvania), Christopher Brown(New York Genome Center), Stephane E. Castel(Chicago Department of Public Health), Lin Chen(James S. McDonnell Foundation), Colby Chiang(Washington University in St. Louis), Donald F. Conrad(Johns Hopkins University), Farhan N. Damani(Stanford University), Joe R. Davis(University of Geneva), Olivier Delaneau(University of Geneva), Emmanouil T. Dermitzakis(Princeton University), Barbara E. Engelhardt(University of California, Los Angeles), Eleazar Eskin(i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto), Pedro G. Ferreira(Stanford University), Laure Frésard(Vanderbilt University Medical Center), Eric R. Gamazon(Barcelona Institute of Science and Technology), Diego Garrido-Martín(Princeton University), Ariel DH Gewirtz(Princeton University), Genna Gliner(Stanford University), Michael J. Gloudemans(Barcelona Institute of Science and Technology), Roderic Guigó(James S. McDonnell Foundation), Ira M. Hall(Ulsan College), Buhm Han(Johns Hopkins University), Yuan He(University of California, Los Angeles), Farhad Hormozdiari(University of Geneva), Cédric Howald(Princeton University), Brian Jo(University of California, Los Angeles), Eun Yong Kang(Johns Hopkins University), Yungil Kim(New York Genome Center), Sarah Kim-Hellmuth(New York Genome Center), Tuuli Lappalainen(University of Geneva), Gen Li(Stanford University), Xin Li(Stanford University), Boxiang Liu(University of California, Los Angeles), Serghei Mangul(Centre for Human Genetics), Mark I. McCarthy(Duke University), Ian C. McDowell(New York Genome Center), Pejman Mohammadi(Barcelona Institute of Science and Technology), Jean Monlong(Stanford University), Stephen B. Montgomery(Barcelona Institute of Science and Technology), Manuel Muñoz-Aguirre(Centre for Human Genetics), Anne W. Ndungu(University of North Carolina at Chapel Hill), Andrew B. Nobel(University of Chicago), Meritxell Oliva(University of Geneva), Halit Ongen(University of North Carolina at Chapel Hill), John Palowitch(University of Geneva), Nikolaos Panousis(Barcelona Institute of Science and Technology), Panagiotis Papasaikas(University of Pennsylvania), YoSon Park(Johns Hopkins University), Princy Parsana(Centre for Human Genetics), A. J. Payne(The University of Texas MD Anderson Cancer Center), Christine B. Peterson(Pfizer (United States)), Jie Quan(Barcelona Institute of Science and Technology), Ferrán Reverter(Stanford University), Chiara Sabatti(Johns Hopkins University), Ashis Saha(Universidade Federal do Rio de Janeiro), Michael Sammeth(James S. McDonnell Foundation), Alexandra J. Scott(University of Utah), Andrey A. Shabalin(Barcelona Institute of Science and Technology), Reza Sodaei(University of Chicago), Matthew Stephens(University of Chicago), Barbara E. Stranger(Johns Hopkins University), Benjamin J. Strober(University of California, Los Angeles), Jae Hoon Sul(Stanford University), Emily K. Tsang(University of Chicago), Sarah Urbut(Centre for Human Genetics), Martijn van de Bunt(University of Chicago), Gao Wang(University of Michigan), Xiaoquan Wen(North Carolina State University), Fred A. Wright(Pfizer (United States)), Hualin Simon Xi(Ben-Gurion University of the Negev), Esti Yeger‐Lotem(Stanford University), Zachary Zappala(European Molecular Biology Laboratory), Judith B. Zaugg(North Carolina State University), Yi‐Hui Zhou(Princeton University), Enhancing GTEx (eGTEx) groups(Altius Institute for Biomedical Sciences), Joshua M. Akey(Stanford University), Daniel J. Bates(Chicago Department of Public Health), Joanne Chan(Broad Institute), Lin Chen(Chicago Department of Public Health), Melina Claussnitzer(Altius Institute for Biomedical Sciences), Kathryn Demanelis(University of Utah), Morgan Diegel(Johns Hopkins University), Jennifer A. Doherty(University of Chicago), Andrew P. Feinberg(Altius Institute for Biomedical Sciences), Marian S. Fernando(Johns Hopkins University), Jessica Halow(Altius Institute for Biomedical Sciences), Kasper D. Hansen(Johns Hopkins University), Eric Haugen(Broad Institute), Peter F. Hickey(Chicago Department of Public Health), Lei Hou(Stanford University), Farzana Jasmine(Stanford University), Ruiqi Jian(Altius Institute for Biomedical Sciences), Lihua Jiang(Altius Institute for Biomedical Sciences), Audra Johnson(Broad Institute), Rajinder Kaul(Chicago Department of Public Health), Manolis Kellis(Altius Institute for Biomedical Sciences), Muhammad G. Kibriya(Stanford University), Kristen Lee(Stanford University), Jin Billy Li(Stanford University), Qin Li(Stanford University), Xiao Li(Stanford University), Jessica Lin(Stanford University), Shin Lin(University of Chicago), Sandra E. Linder(Massachusetts Institute of Technology), Caroline Linke(NYU Langone Health), Yaping Liu(Broad Institute), Matthew T. Maurano(Stanford University), Benoit Molinié(Altius Institute for Biomedical Sciences), Stephen B. Montgomery(Altius Institute for Biomedical Sciences), Jemma Nelson(University of Chicago), Fidencio Neri(Massachusetts Institute of Technology), Meritxell Oliva(Chicago Department of Public Health), Yongjin Park(Massachusetts Institute of Technology), Brandon L. Pierce(Johns Hopkins University), Nicola J. Rinaldi(Altius Institute for Biomedical Sciences), Lindsay F. Rizzardi(University of Chicago), Richard Sandstrom(Stanford University), Andrew D. Skol(Stanford University), Kevin S. Smith(Altius Institute for Biomedical Sciences), M Snyder(University of Chicago), J Stamatoyannopoulos(Stanford University), Barbara E. Stranger(Stanford University), Hua Tang(Broad Institute), Emily K. Tsang(Stanford University), Li Wang(Broad Institute), Meng Wang(University of Chicago), Nicholas Van Wittenberghe(Stanford University), Fan Wu(Office of the Director), Rui Zhang(National Cancer Institute), NIH Common Fund(National Cancer Institute), Concepcion R. Nierras(National Cancer Institute), NIH/NCI(National Cancer Institute), Philip A. Branton(National Cancer Institute), Latarsha J. Carithers(National Cancer Institute), Ping Guan(National Human Genome Research Institute), Helen M. Moore(National Human Genome Research Institute), Abhi K. Rao(National Human Genome Research Institute), Jimmie B. Vaught(National Human Genome Research Institute), NIH/NHGrI(National Human Genome Research Institute), Sarah E. Gould(National Institute of Mental Health), Nicole C. Lockart(National Institute of Mental Health), Casey Martin(National Institute on Drug Abuse), Jeffery P. Struewing, Simona Volpi(Gift of Life Michigan), NIH/NIMH, Anjené Addington(Organ Recovery Systems (United States)), Susan E. Koester(Lifenet Health), NIH/NIDA, A. Roger Little, Biospecimen Collection Source Site—NDrI, Lori E. Brigham, Richard Hasz, Marcus Anthony Hunter, Christopher Johns, Mark R. Johnson, Gene Kopen, William F. Leinweber, John T. Lonsdale(Lifenet Health), Alisa McDonald(Lifenet Health), Bernadette Mestichelli(Organ Recovery Systems (United States)), Kevin Myer, Brian Roe(Roswell Park Comprehensive Cancer Center), Michael F. Salvatore(Roswell Park Comprehensive Cancer Center), Saboor Shad(Roswell Park Comprehensive Cancer Center), Jeffrey A. Thomas(Roswell Park Comprehensive Cancer Center), Gary Walters, Michael Washington(Roswell Park Comprehensive Cancer Center), J. Gary Wheeler(Van Andel Institute), Biospecimen Collection Source Site—rPCI(Van Andel Institute), Jason Bridge(Van Andel Institute), Barbara A. Foster(Van Andel Institute), Bryan M. Gillard(University of Miami), Ellen Karasik(University of Miami), Rachna Kumar(National Institute of Allergy and Infectious Diseases), Mark Miklos(Leidos (United States)), Michael T. Moser(Leidos (United States)), Biospecimen Core resource—VArI(Leidos (United States)), Scott D. Jewell(Leidos (United States)), Robert G. Montroy(Leidos (United States)), Daniel C. Rohrer(Leidos (United States)), Dana R. Valley(Leidos (United States)), David A. Davis(Leidos (United States)), Deborah C. Mash(Leidos (United States)), Leidos Biomedical—Project Management(Leidos (United States)), Anita H. Undale(Leidos (United States)), Anna Marie Smith(Leidos (United States)), David E. Tabor(Leidos (United States)), Nancy Roche(Leidos (United States)), Jeffrey A. McLean(Leidos (United States)), Negin Vatanian(Leidos (United States)), Karna Robinson(Temple University), Leslie H. Sobin(Virginia Commonwealth University), Mary E. Barcus(Temple University), Kimberly M. Valentino(Temple University), Liqun Qi(European Bioinformatics Institute), Steven Hunter(European Bioinformatics Institute), Pushpa Hariharan(European Bioinformatics Institute), Shilpi Singh(European Bioinformatics Institute), Ki Sung Um(European Bioinformatics Institute), Takunda Matose(European Bioinformatics Institute), M. Tomaszewski(European Bioinformatics Institute), ELSI Study(University of California, Santa Cruz), Laura K. Barker(University of California, Santa Cruz), Maghboeba Mosavel(University of California, Santa Cruz), Laura A. Siminoff(University of California, Santa Cruz), Heather M. Traino(University of California, Santa Cruz), Genome Browser Data Integration & Visualization—EBI(University of California, Santa Cruz), Paul Flicek(University of California, Santa Cruz), Thomas Juettemann(University of California, Santa Cruz), Magali Ruffier(University of California, Santa Cruz), Dan Sheppard(University of Chicago), Kieron Taylor(Vanderbilt University Medical Center), Stephen J. Trevanion(University of Chicago), Daniel R. Zerbino, Brian Craft, Mary J. Goldman, Maximilian Haeussler, W. James Kent, Christopher M. Lee, Benedict Paten, Kate R. Rosenbloom, John Vivian, Jingchun Zhu, Dan L. Nicolae(University of Chicago), Nancy J. Cox(Vanderbilt University Medical Center), Hae Kyung Im(University of Chicago)
Cited by 1,215Open Access
Abstract
Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
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