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.
| Original language | English (US) |
|---|---|
| Article number | 1825 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
| Externally published | Yes |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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In: Nature communications, Vol. 9, No. 1, 1825, 01.12.2018.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
AU - Barbeira, Alvaro N.
AU - Dickinson, Scott P.
AU - Bonazzola, Rodrigo
AU - Zheng, Jiamao
AU - Wheeler, Heather E.
AU - Torres, Jason M.
AU - Torstenson, Eric S.
AU - Shah, Kaanan P.
AU - Garcia, Tzintzuni
AU - Edwards, Todd L.
AU - Stahl, Eli A.
AU - Huckins, Laura M.
AU - Aguet, François
AU - Ardlie, Kristin G.
AU - Cummings, Beryl B.
AU - Gelfand, Ellen T.
AU - Getz, Gad
AU - Hadley, Kane
AU - Handsaker, Robert E.
AU - Huang, Katherine H.
AU - Kashin, Seva
AU - Karczewski, Konrad J.
AU - Lek, Monkol
AU - Li, Xiao
AU - MacArthur, Daniel G.
AU - Nedzel, Jared L.
AU - Nguyen, Duyen T.
AU - Noble, Michael S.
AU - Segrè, Ayellet V.
AU - Trowbridge, Casandra A.
AU - Tukiainen, Taru
AU - Abell, Nathan S.
AU - Balliu, Brunilda
AU - Barshir, Ruth
AU - Basha, Omer
AU - Battle, Alexis
AU - Bogu, Gireesh K.
AU - Brown, Andrew
AU - Brown, Christopher D.
AU - Castel, Stephane E.
AU - Chen, Lin S.
AU - Chiang, Colby
AU - Conrad, Donald F.
AU - Damani, Farhan N.
AU - Davis, Joe R.
AU - Delaneau, Olivier
AU - Dermitzakis, Emmanouil T.
AU - Engelhardt, Barbara E.
AU - Eskin, Eleazar
AU - Ferreira, Pedro G.
AU - Frésard, Laure
AU - Gamazon, Eric R.
AU - Garrido-Martín, Diego
AU - Gewirtz, Ariel D.H.
AU - Gliner, Genna
AU - Gloudemans, Michael J.
AU - Guigo, Roderic
AU - Hall, Ira M.
AU - Han, Buhm
AU - He, Yuan
AU - Hormozdiari, Farhad
AU - Howald, Cedric
AU - Jo, Brian
AU - Kang, Eun Yong
AU - Kim, Yungil
AU - Kim-Hellmuth, Sarah
AU - Lappalainen, Tuuli
AU - Li, Gen
AU - Li, Xin
AU - Liu, Boxiang
AU - Mangul, Serghei
AU - McCarthy, Mark I.
AU - McDowell, Ian C.
AU - Mohammadi, Pejman
AU - Monlong, Jean
AU - Montgomery, Stephen B.
AU - Muñoz-Aguirre, Manuel
AU - Ndungu, Anne W.
AU - Nobel, Andrew B.
AU - Oliva, Meritxell
AU - Ongen, Halit
AU - Palowitch, John J.
AU - Panousis, Nikolaos
AU - Papasaikas, Panagiotis
AU - Park, Yo Son
AU - Parsana, Princy
AU - Payne, Anthony J.
AU - Peterson, Christine B.
AU - Quan, Jie
AU - Reverter, Ferran
AU - Sabatti, Chiara
AU - Saha, Ashis
AU - Sammeth, Michael
AU - Scott, Alexandra J.
AU - Shabalin, Andrey A.
AU - Sodaei, Reza
AU - Stephens, Matthew
AU - Stranger, Barbara E.
AU - Strober, Benjamin J.
AU - Sul, Jae Hoon
AU - Tsang, Emily K.
AU - Urbut, Sarah
AU - Van De Bunt, Martijn
AU - Wang, Gao
AU - Wen, Xiaoquan
AU - Wright, Fred A.
AU - Xi, Hualin S.
AU - Yeger-Lotem, Esti
AU - Zappala, Zachary
AU - Zaugg, Judith B.
AU - Zhou, Yi Hui
AU - Akey, Joshua M.
AU - Bates, Daniel
AU - Chan, Joanne
AU - Claussnitzer, Melina
AU - Demanelis, Kathryn
AU - Diegel, Morgan
AU - Doherty, Jennifer A.
AU - Feinberg, Andrew P.
AU - Fernando, Marian S.
AU - Halow, Jessica
AU - Hansen, Kasper D.
AU - Haugen, Eric
AU - Hickey, Peter F.
AU - Hou, Lei
AU - Jasmine, Farzana
AU - Jian, Ruiqi
AU - Jiang, Lihua
AU - Johnson, Audra
AU - Kaul, Rajinder
AU - Kellis, Manolis
AU - Kibriya, Muhammad G.
AU - Lee, Kristen
AU - Li, Jin Billy
AU - Li, Qin
AU - Lin, Jessica
AU - Lin, Shin
AU - Linder, Sandra
AU - Linke, Caroline
AU - Liu, Yaping
AU - Maurano, Matthew T.
AU - Molinie, Benoit
AU - Nelson, Jemma
AU - Neri, Fidencio J.
AU - Park, Yongjin
AU - Pierce, Brandon L.
AU - Rinaldi, Nicola J.
AU - Rizzardi, Lindsay F.
AU - Sandstrom, Richard
AU - Skol, Andrew
AU - Smith, Kevin S.
AU - Snyder, Michael P.
AU - Stamatoyannopoulos, John
AU - Tang, Hua
AU - Wang, Li
AU - Wang, Meng
AU - Van Wittenberghe, Nicholas
AU - Wu, Fan
AU - Zhang, Rui
AU - Nierras, Concepcion R.
AU - Branton, Philip A.
AU - Carithers, Latarsha J.
AU - Guan, Ping
AU - Moore, Helen M.
AU - Rao, Abhi
AU - Vaught, Jimmie B.
AU - Gould, Sarah E.
AU - Lockart, Nicole C.
AU - Martin, Casey
AU - Struewing, Jeffery P.
AU - Volpi, Simona
AU - Addington, Anjene M.
AU - Koester, Susan E.
AU - Little, A. Roger
AU - Brigham, Lori E.
AU - Hasz, Richard
AU - Hunter, Marcus
AU - Johns, Christopher
AU - Johnson, Mark
AU - Kopen, Gene
AU - Leinweber, William F.
AU - Lonsdale, John T.
AU - McDonald, Alisa
AU - Mestichelli, Bernadette
AU - Myer, Kevin
AU - Roe, Brian
AU - Salvatore, Michael
AU - Shad, Saboor
AU - Thomas, Jeffrey A.
AU - Walters, Gary
AU - Washington, Michael
AU - Wheeler, Joseph
AU - Bridge, Jason
AU - Foster, Barbara A.
AU - Gillard, Bryan M.
AU - Karasik, Ellen
AU - Kumar, Rachna
AU - Miklos, Mark
AU - Moser, Michael T.
AU - Jewell, Scott D.
AU - Montroy, Robert G.
AU - Rohrer, Daniel C.
AU - Valley, Dana R.
AU - Davis, David A.
AU - Mash, Deborah C.
AU - Undale, Anita H.
AU - Smith, Anna M.
AU - Tabor, David E.
AU - Roche, Nancy V.
AU - McLean, Jeffrey A.
AU - Vatanian, Negin
AU - Robinson, Karna L.
AU - Sobin, Leslie
AU - Barcus, Mary E.
AU - Valentino, Kimberly M.
AU - Qi, Liqun
AU - Hunter, Steven
AU - Hariharan, Pushpa
AU - Singh, Shilpi
AU - Um, Ki Sung
AU - Matose, Takunda
AU - Tomaszewski, Maria M.
AU - Barker, Laura K.
AU - Mosavel, Maghboeba
AU - Siminoff, Laura A.
AU - Traino, Heather M.
AU - Flicek, Paul
AU - Juettemann, Thomas
AU - Ruffier, Magali
AU - Sheppard, Dan
AU - Taylor, Kieron
AU - Trevanion, Stephen J.
AU - Zerbino, Daniel R.
AU - Craft, Brian
AU - Goldman, Mary
AU - Haeussler, Maximilian
AU - Kent, W. James
AU - Lee, Christopher M.
AU - Paten, Benedict
AU - Rosenbloom, Kate R.
AU - Vivian, John
AU - Zhu, Jingchun
AU - Nicolae, Dan L.
AU - Cox, Nancy J.
AU - Im, Hae Kyung
N1 - Publisher Copyright: © 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046840811&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046840811&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03621-1
DO - 10.1038/s41467-018-03621-1
M3 - Article
C2 - 29739930
AN - SCOPUS:85046840811
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1825
ER -