Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

• DOI: 10.1038/s41467-018-03621-1
• Publication Date: 2018-05-02T10:42:16Z
• 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. Trowb...; Taru Tukiainen; ; 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. Derm...; Barbara E. Engelh...; Eleazar Eskin; Pedro G. Ferreira; Laure Frésard; Eric R. Gamazon; Diego Garrido-Martín; Ariel D. H. Gewirtz; Genna Gliner; Michael J. Gloude...; 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. Montgo...; Manuel Muñoz-Aguirre; Anne W. Ndungu; Andrew B. Nobel; Meritxell Oliva; Halit Ongen; John J. Palowitch; Nikolaos Panousis; Panagiotis Papasa...; YoSon Park; Princy Parsana; Anthony J. Payne; Christine B. Pete...; 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; ; 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. Montgo...; 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 Stamatoyanno...; Barbara E. Stranger; Hua Tang; Emily K. Tsang; Li Wang; Meng Wang; Nicholas Van Witt...; Fan Wu; Rui Zhang; ; Concepcion R. Nie...; ; Philip A. Branton; Latarsha J. Carit...; Ping Guan; Helen M. Moore; Abhi Rao; Jimmie B. Vaught; ; Sarah E. Gould; Nicole C. Lockart; Casey Martin; Jeffery P. Struewing; Simona Volpi; ; Anjene M. Addington; Susan E. Koester; ; A. Roger Little; ; Lori E. Brigham; Richard Hasz; Marcus Hunter; Christopher Johns; Mark Johnson; Gene Kopen; William F. Leinweber; John T. Lonsdale; Alisa McDonald; Bernadette Mestic...; Kevin Myer; Brian Roe; Michael Salvatore; Saboor Shad; Jeffrey A. Thomas; Gary Walters; Michael Washington; Joseph Wheeler; ; Jason Bridge; Barbara A. Foster; Bryan M. Gillard; Ellen Karasik; Rachna Kumar; Mark Miklos; Michael T. Moser; ; Scott D. Jewell; Robert G. Montroy; Daniel C. Rohrer; Dana R. Valley; ; David A. Davis; Deborah C. Mash; ; 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. Valen...; Liqun Qi; Steven Hunter; Pushpa Hariharan; Shilpi Singh; Ki Sung Um; Takunda Matose; Maria M. Tomaszewski; ; Laura K. Barker; Maghboeba Mosavel; Laura A. Siminoff; Heather M. Traino; ; 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
• Keywords: Genome-wide Association Study; Variation (astronomy); Summary statistics

Abstract Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy general robustness misspecified reference sets. We apply this framework 44 GTEx tissues 100+ from GWAS meta-analysis studies, creating growing public catalog of associations seeks capture the effects variation on human phenotypes. Replication in an independent cohort is shown. Most tissue specific, suggesting context specificity trait etiology. Colocalized significant unexpected underscore need for agnostic scanning multiple contexts improve our ability detect causal regulatory mechanisms. Monogenic disease genes enriched among related traits, smaller alterations these may cause spectrum milder