Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
Authors: Barbeira Alvaro N. , Dickinson Scott P. , Bonazzola Rodrigo , Zheng Jiamao , Wheeler Heather E. , Torres Jason M. , Torstenson Eric S. , Shah Kaanan P. , Garcia Tzintzuni , Edwards Todd L. , Stahl Eli A. , Huckins Laura M. ,   GTEx Consortium,   Laboratory, Data Analysis & Coordinating Center (LDACC)—Analysis Working Group, Aguet François , Ardlie Kristin G. , Cummings Beryl B. , Gelfand Ellen T. , Getz Gad , Hadley Kane , Handsaker Robert E. , Huang Katherine H. , Kashin Seva , Karczewski Konrad J. , Lek Monkol , Li Xiao , MacArthur Daniel G. , Nedzel Jared L. , Nguyen Duyen T. , Noble Michael S. , Segrè Ayellet V. , Trowbridge Casandra A. , Tukiainen Taru ,   Statistical Methods groups—Analysis Working Group, Abell Nathan S. , Balliu Brunilda , Barshir Ruth , Basha Omer , Battle Alexis , Bogu Gireesh K. , Brown Andrew , Brown Christopher D. , Castel Stephane E. , Chen Lin S. , Chiang Colby , Conrad Donald F. , Damani Farhan N. , Davis Joe R. , Delaneau Olivier , Dermitzakis Emmanouil T. , Engelhardt Barbara E. , Eskin Eleazar , Ferreira Pedro G. , Frésard Laure , Gamazon Eric R. , Garrido-Martín Diego , Gewirtz Ariel D. H. , Gliner Genna , Gloudemans Michael J. , Guigo Roderic , Hall Ira M. , Han Buhm , He Yuan , Hormozdiari Farhad , Howald Cedric , Jo Brian , Kang Eun Yong , Kim Yungil , Kim-Hellmuth Sarah , Lappalainen Tuuli , Li Gen , Li Xin , Liu Boxiang , Mangul Serghei , McCarthy Mark I. , McDowell Ian C. , Mohammadi Pejman , Monlong Jean , Montgomery Stephen B. , Muñoz-Aguirre Manuel , Ndungu Anne W. , Nobel Andrew B. , Oliva Meritxell , Ongen Halit , Palowitch John J. , Panousis Nikolaos , Papasaikas Panagiotis , Park YoSon , Parsana Princy , Payne Anthony J. , Peterson Christine B. , Quan Jie , Reverter Ferran , Sabatti Chiara , Saha Ashis , Sammeth Michael , Scott Alexandra J. , Shabalin Andrey A. , Sodaei Reza , Stephens Matthew , Stranger Barbara E. , Strober Benjamin J. , Sul Jae Hoon , Tsang Emily K. , Urbut Sarah , van de Bunt Martijn , Wang Gao , Wen Xiaoquan , Wright Fred A. , Xi Hualin S. , Yeger-Lotem Esti , Zappala Zachary , Zaugg Judith B. , Zhou Yi-Hui ,   Enhancing GTEx (eGTEx) groups, Akey Joshua M. , Bates Daniel , Chan Joanne , Chen Lin S. , Claussnitzer Melina , Demanelis Kathryn , Diegel Morgan , Doherty Jennifer A. , Feinberg Andrew P. , Fernando Marian S. , Halow Jessica , Hansen Kasper D. , Haugen Eric , Hickey Peter F. , Hou Lei , Jasmine Farzana , Jian Ruiqi , Jiang Lihua , Johnson Audra , Kaul Rajinder , Kellis Manolis , Kibriya Muhammad G. , Lee Kristen , Li Jin Billy , Li Qin , Li Xiao , Lin Jessica , Lin Shin , Linder Sandra , Linke Caroline , Liu Yaping , Maurano Matthew T. , Molinie Benoit , Montgomery Stephen B. , Nelson Jemma , Neri Fidencio J. , Oliva Meritxell , Park Yongjin , Pierce Brandon L. , Rinaldi Nicola J. , Rizzardi Lindsay F. , Sandstrom Richard , Skol Andrew , Smith Kevin S. , Snyder Michael P. , Stamatoyannopoulos John , Stranger Barbara E. , Tang Hua , Tsang Emily K. , Wang Li , Wang Meng , Van Wittenberghe Nicholas , Wu Fan , Zhang Rui ,   NIH Common Fund, Nierras Concepcion R. ,   NIH/NCI, Branton Philip A. , Carithers Latarsha J. , Guan Ping , Moore Helen M. , Rao Abhi , Vaught Jimmie B. ,   NIH/NHGrI, Gould Sarah E. , Lockart Nicole C. , Martin Casey , Struewing Jeffery P. , Volpi Simona ,   NIH/NIMH, Addington Anjene M. , Koester Susan E. ,   NIH/NIDA, Little A. Roger ,   Biospecimen Collection Source Site—NDrI, Brigham Lori E. , Hasz Richard , Hunter Marcus , Johns Christopher , Johnson Mark , Kopen Gene , Leinweber William F. , Lonsdale John T. , McDonald Alisa , Mestichelli Bernadette , Myer Kevin , Roe Brian , Salvatore Michael , Shad Saboor , Thomas Jeffrey A. , Walters Gary , Washington Michael , Wheeler Joseph ,   Biospecimen Collection Source Site—rPCI, Bridge Jason , Foster Barbara A. , Gillard Bryan M. , Karasik Ellen , Kumar Rachna , Miklos Mark , Moser Michael T. ,   Biospecimen Core resource—VArI, Jewell Scott D. , Montroy Robert G. , Rohrer Daniel C. , Valley Dana R. ,   Brain Bank repository—University of Miami Brain Endowment Bank, Davis David A. , Mash Deborah C. ,   Leidos Biomedical—Project Management, Undale Anita H. , Smith Anna M. , Tabor David E. , Roche Nancy V. , McLean Jeffrey A. , Vatanian Negin , Robinson Karna L. , Sobin Leslie , Barcus Mary E. , Valentino Kimberly M. , Qi Liqun , Hunter Steven , Hariharan Pushpa , Singh Shilpi , Um Ki Sung , Matose Takunda , Tomaszewski Maria M. ,   ELSI Study, Barker Laura K. , Mosavel Maghboeba , Siminoff Laura A. , Traino Heather M. ,   Genome Browser Data Integration & Visualization—EBI, Flicek Paul , Juettemann Thomas , Ruffier Magali , Sheppard Dan , Taylor Kieron , Trevanion Stephen J. , Zerbino Daniel R. ,   Genome Browser Data Integration & Visualization—UCSC Genomics Institute, University of California Santa Cruz, Craft Brian , Goldman Mary , Haeussler Maximilian , Kent W. James , Lee Christopher M. , Paten Benedict , Rosenbloom Kate R. , Vivian John , Zhu Jingchun , Nicolae Dan L. , Cox Nancy J. , Im Hae Kyung 
Published: May 2018

AbstractScalable, 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.