Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
Year: 2018
Type: article
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.
Source: Nature Communications
Authors: Alvaro N. Barbeira, Scott P. Dickinson, Rodrigo Bonazzola, Jiamao Zheng, Heather E. Wheeler, Jason M. Torres, Eric S. Torstenson, Kaanan P. Shah, Tzintzuni Garcia, Todd L. Edwards, Eli A. Stahl, Laura M. Huckins, François Aguet, Kristin G. Ardlie, Beryl B. Cummings, Ellen T. Gelfand, Gad Getz, Kane Hadley, Robert E. Handsaker, Katherine H. Huang, Seva Kashin, Konrad J. Karczewski, Monkol Lek, Xiao Li, Daniel G. MacArthur, Jared L. Nedzel, Duyen T. Nguyen, Michael S. Noble, Ayellet V. Segrè, Casandra A. Trowbridge, Taru Tukiainen, Statistical Methods groups—Analysis Working Group, Nathan S. Abell, Brunilda Balliu, Ruth Barshir, Omer Basha, Alexis Battle, Gireesh K. Bogu, Andrew Brown, Christopher D. Brown, Stephane E. Castel, Lin S. Chen, Colby Chiang, Donald F. Conrad, Farhan N. Damani, Joe R. Davis, Olivier Delaneau, Emmanouil T. Dermitzakis, Barbara E. Engelhardt, Eleazar Eskin, Pedro G. Ferreira, Laure Frésard, Eric R. Gamazon, Diego Garrido-Martín, Ariel D. H. Gewirtz, Genna Gliner, Michael J. Gloudemans, Roderic Guigo, Ira M. Hall, Buhm Han, Yuan He, Farhad Hormozdiari, Cedric Howald, Brian Jo, Eun Yong Kang, Yungil Kim, Sarah Kim-Hellmuth, Tuuli Lappalainen, Gen Li, Xin Li, Boxiang Liu, Serghei Mangul, Mark I. McCarthy, Ian C. McDowell, Pejman Mohammadi, Jean Monlong, Stephen B. Montgomery, Manuel Muñoz-Aguirre, Anne W. Ndungu, Andrew B. Nobel, Meritxell Oliva, Halit Ongen, John J. Palowitch, Nikolaos Panousis, Panagiotis Papasaikas, YoSon Park, Princy Parsana, Anthony J. Payne, Christine B. Peterson, Jie Quan, Ferran Reverter, Chiara Sabatti, Ashis Saha, Michael Sammeth, Alexandra J. Scott, Andrey A. Shabalin, Reza Sodaei, Matthew Stephens, Barbara E. Stranger, Benjamin J. Strober, Jae Hoon Sul, Emily K. Tsang, Sarah Urbut, Martijn van de Bunt, Gao Wang, Xiaoquan Wen, Fred A. Wright, Hualin S. Xi, Esti Yeger-Lotem, Zachary Zappala, Judith B. Zaugg, Yi-Hui Zhou, Enhancing GTEx (eGTEx) groups, Joshua M. Akey, Daniel Bates, Joanne Chan, Lin S. Chen, Melina Claussnitzer, Kathryn Demanelis, Morgan Diegel, Jennifer A. Doherty, Andrew P. Feinberg, Marian S. Fernando, Jessica Halow, Kasper D. Hansen, Eric Haugen, Peter F. Hickey, Lei Hou, Farzana Jasmine, Ruiqi Jian, Lihua Jiang, Audra Johnson, Rajinder Kaul, Manolis Kellis, Muhammad G. Kibriya, Kristen Lee, Jin Billy Li, Qin Li, Xiao Li, Jessica Lin, Shin Lin, Sandra Linder, Caroline Linke, Yaping Liu, Matthew T. Maurano, Benoit Molinie, Stephen B. Montgomery, Jemma Nelson, Fidencio J. Neri, Meritxell Oliva, Yongjin Park, Brandon L. Pierce, Nicola J. Rinaldi, Lindsay F. Rizzardi, Richard Sandstrom, Andrew Skol, Kevin S. Smith, Michael P. Snyder, John Stamatoyannopoulos, Barbara E. Stranger, Hua Tang, Emily K. Tsang, Li Wang, Meng Wang, Nicholas Van Wittenberghe, Fan Wu, Rui Zhang, NIH Common Fund, Concepcion R. Nierras, NIH/NCI, Philip A. Branton, Latarsha J. Carithers, Ping Guan, Helen M. Moore, Abhi Rao, Jimmie B. Vaught, NIH/NHGrI, Sarah E. Gould, Nicole C. Lockart, Casey Martin, Jeffery P. Struewing, Simona Volpi, NIH/NIMH, Anjene M. Addington, Susan E. Koester, NIH/NIDA, A. Roger Little, Biospecimen Collection Source Site—NDrI, Lori E. Brigham, Richard Hasz, Marcus Hunter, Christopher Johns, Mark Johnson, Gene Kopen, William F. Leinweber, John T. Lonsdale, Alisa McDonald, Bernadette Mestichelli, Kevin Myer, Brian Roe, Michael Salvatore, Saboor Shad, Jeffrey A. Thomas, Gary Walters, Michael Washington, Joseph Wheeler, Biospecimen Collection Source Site—rPCI, Jason Bridge, Barbara A. Foster, Bryan M. Gillard, Ellen Karasik, Rachna Kumar, Mark Miklos, Michael T. Moser, Biospecimen Core resource—VArI, Scott D. Jewell, Robert G. Montroy, Daniel C. Rohrer, Dana R. Valley, David A. Davis, Deborah C. Mash, Leidos Biomedical—Project Management, Anita H. Undale, Anna M. Smith, David E. Tabor, Nancy V. Roche, Jeffrey A. McLean, Negin Vatanian, Karna L. Robinson, Leslie Sobin, Mary E. Barcus, Kimberly M. Valentino, Liqun Qi, Steven Hunter, Pushpa Hariharan, Shilpi Singh, Ki Sung Um, Takunda Matose, Maria M. Tomaszewski, ELSI Study, Laura K. Barker, Maghboeba Mosavel, Laura A. Siminoff, Heather M. Traino, Genome Browser Data Integration & Visualization—EBI, Paul Flicek, Thomas Juettemann, Magali Ruffier, Dan Sheppard, Kieron Taylor, Stephen J. Trevanion, Daniel R. Zerbino, Brian Craft, Mary Goldman, Maximilian Haeussler, W. James Kent, Christopher M. Lee, Benedict Paten, Kate R. Rosenbloom, John Vivian, Jingchun Zhu, Dan L. Nicolae, Nancy J. Cox, Hae Kyung Im
Institutions: University of Chicago, Loyola University Chicago, Vanderbilt University Medical Center, Vanderbilt University, Icahn School of Medicine at Mount Sinai, Broad Institute, Harvard University, Massachusetts Institute of Technology, Massachusetts General Hospital, Stanford University, Ben-Gurion University of the Negev, Johns Hopkins University, Universitat Pompeu Fabra, Barcelona Institute of Science and Technology, Centre for Genomic Regulation, University of Geneva, SIB Swiss Institute of Bioinformatics, Institute of Genetics and Genomics in Geneva, University of Pennsylvania, Columbia University Irving Medical Center, New York Genome Center, Washington University in St. Louis, Princeton University, University of California, Los Angeles, Universidade do Porto, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Amsterdam UMC Location University of Amsterdam, University of Amsterdam, Hospital del Mar Research Institute, Asan Medical Center, University of Ulsan, Columbia University, Centre for Human Genetics, Churchill Hospital, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism, Duke University, McGill University, Universitat Politècnica de Catalunya, University of North Carolina at Chapel Hill, MIT Computer Science and Artificial Intelligence Laboratory, The University of Texas MD Anderson Cancer Center, Pfizer (United States), Universitat de Barcelona, Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, University of Utah, University of Michigan, North Carolina State University, European Molecular Biology Laboratory, Altius Institute for Biomedical Sciences, University of Hohenheim, Beth Israel Deaconess Medical Center, Huntsman Cancer Institute, Johns Hopkins Medicine, University of Washington, NYU Langone Health, National Institutes of Health, Office of the Director, Division of Program Coordination Planning and Strategic Initiatives, National Cancer Institute, National Institute of Dental and Craniofacial Research, National Human Genome Research Institute, National Institute of Mental Health, National Institute on Drug Abuse, Lifenet Health, National Disease Research Interchange, University at Buffalo, State University of New York, Roswell Park Comprehensive Cancer Center, Van Andel Institute, University of Miami, National Institute of Allergy and Infectious Diseases, Leidos Biomedical Research Inc. (United States), Temple University, Virginia Commonwealth University, European Bioinformatics Institute, University of California, Santa Cruz
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: University of Miami, University of Pennsylvania, Harvard University, Loyola University Chicago, Georgia Clinical and Translational Science Alliance, Université de Genève, National Institutes of Health, Medical Research Council, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Common Fund
Awards: Methods for high-resolution analysis of genetic effects on gene expression, Training in Emerging Multidisciplinary Approaches to Mental Health and Disease, Identification and validation of cell specific eQTLs by Bayesian modeling, Using the Transcriptome for SNP and Gene Annotation, Predicted Gene Expression: High Power, Mechanism, and Direction of Effect, MODELING THE EFFECTS OF STRUCTURAL VARIATION IN GTEX DATA AND MENDELIAN DISEASE, Epigenetic Marks of Cocaine Addiction, G3445821079, Re-Engineering Translational Research at the University of Chicago, Genetic Regulation of Gene Expression and its Impact on Phenotypes, Systems approaches to link tissue-specific expression to disease, Harnessing GTEx to Create Transcriptome Knowledge and Inform Disease Biology, Epistatic and Cross Tissue Analysis for Human Gene Expression Traits, Predicting gene regulation across populations to understand mechanisms underlying complex traits, Conte Center for Computational Systems Genomics of Neuropsychiatric Phenotypes, Statistical analysis of gene expression quantitative trait loci (eQTL), Methods for high-resolution analysis of genetic effects on gene expression, Leveraging functional genetic variation to elucidate the genetic architecture of, FACILITATING GTEx, DISEASE, AND GxE ANALYSES VIA FAST EXPRESSION (e)QTL MAPPING, Statistical analysis of gene expression quantitative trait loci (eQTL), CNS Mechanisms in Cocaine-Related Sudden Death, Center for Genetic Studies of Drug Abuse in Outbred Rats, G8631870757, Diabetes Research and Training Center
OpenAlex ID: W2952346218