Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
Nature Communications2018Vol. 9(1), pp. 1825–1825
Citations Over TimeTop 1% of 2018 papers
Alvaro Barbeira, Scott Dickinson, Rodrigo Bonazzola, Jiamao Zheng, Heather E. Wheeler, Jason Torres, Eric S. Torstenson, Kaanan P. Shah, Tzintzuni Garcia, Todd L. Edwards, Eli A. Stahl, Laura M. Huckins, François Aguet, Kristin Ardlie, Beryl B. Cummings, Ellen Gelfand, Gad Getz, Kane Hadley, Robert E. Handsaker, Katherine 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 Brown, Stephane E. Castel, Lin 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 DH Gewirtz, Genna Gliner, Michael J. Gloudemans, Roderic Guigó, Ira M. Hall, Buhm Han, Yuan He, Farhad Hormozdiari, Cédric 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 Palowitch, Nikolaos Panousis, Panagiotis Papasaikas, YoSon Park, Princy Parsana, A. J. Payne, Christine B. Peterson, Jie Quan, Ferrán 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 Simon Xi, Esti Yeger‐Lotem, Zachary Zappala, Judith B. Zaugg, Yi‐Hui Zhou, Enhancing GTEx (eGTEx) groups, Joshua M. Akey, Daniel J. Bates, Joanne Chan, Lin 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 E. Linder, Caroline Linke, Yaping Liu, Matthew T. Maurano, Benoit Molinié, Stephen B. Montgomery, Jemma Nelson, Fidencio Neri, Meritxell Oliva, Yongjin Park, Brandon L. Pierce, Nicola J. Rinaldi, Lindsay F. Rizzardi, Richard Sandstrom, Andrew D. Skol, Kevin S. Smith, M Snyder, J 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 K. Rao, Jimmie B. Vaught, NIH/NHGrI, Sarah E. Gould, Nicole C. Lockart, Casey Martin, Jeffery P. Struewing, Simona Volpi, NIH/NIMH, Anjené Addington, Susan E. Koester, 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, Alisa McDonald, Bernadette Mestichelli, Kevin Myer, Brian Roe, Michael F. Salvatore, Saboor Shad, Jeffrey A. Thomas, Gary Walters, Michael Washington, J. Gary 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 Marie Smith, David E. Tabor, Nancy Roche, Jeffrey A. McLean, Negin Vatanian, Karna Robinson, Leslie H. Sobin, Mary E. Barcus, Kimberly M. Valentino, Liqun Qi, Steven Hunter, Pushpa Hariharan, Shilpi Singh, Ki Sung Um, Takunda Matose, 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 J. 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
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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