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Local genetic effects on gene expression across 44 human tissues

François Aguet, Andrew A. Brown, Stephane E. Castel, Joe R. Davis, Pejman Mohammadi, Ayellet V. Segrè, Zachary Zappala, Nathan S. Abell, Laure Frésard, Eric R. Gamazon, Ellen Gelfand, Michael J. Gloudemans, Yuan He, Farhad Hormozdiari, Xiao Li, Xin Li, Boxiang Liu, Diego Garrido-Martín, Halit Ongen, John J. Palowitch, YoSon Park, Christine B. Peterson, Gerald Quon, Stephan Ripke, Andrey A. Shabalin, Tyler C. Shimko, Benjamin J. Strober, Timothy J. Sullivan, Nicole A. Teran, Emily K. Tsang, Hailei Zhang, Yi-Hui Zhou, Alexis Battle, Carlos D. Bustamonte, Nancy J. Cox, Barbara E. Engelhardt, Eleazar Eskin, Gad Getz, Manolis Kellis, Gen Li, Daniel G. MacArthur, Andrew B. Nobel, Chiara Sabbati, Xiaoquan Wen, Fred A. Wright, GTEx Consortium, Tuuli Lappalainen, Kristin G. Ardlie, Emmanouil T. Dermitzakis, View ORCID ProfileChristopher D. Brown, Stephen B. Montgomery
doi: https://doi.org/10.1101/074450
François Aguet
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Andrew A. Brown
2Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
3Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
4Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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Stephane E. Castel
5New York Genome Center, New York, NY, 10013, USA
6Department of Systems Biology, Columbia University, New York, NY, 10032, USA
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Joe R. Davis
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Pejman Mohammadi
5New York Genome Center, New York, NY, 10013, USA
6Department of Systems Biology, Columbia University, New York, NY, 10032, USA
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Ayellet V. Segrè
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Zachary Zappala
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Nathan S. Abell
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Laure Frésard
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Eric R. Gamazon
9Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, 37232, USA
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Ellen Gelfand
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Michael J. Gloudemans
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
10Biomedical Informatics Program, Stanford University, Stanford, CA, 94305, USA
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Yuan He
11Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
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Farhad Hormozdiari
12Department of Human Genetics, University of California, Los Angeles, CA, 90095, USA
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Xiao Li
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Xin Li
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Boxiang Liu
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
13Department of Biology, Stanford University, Stanford, CA, 94305, USA
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Diego Garrido-Martín
14Bioinformatics and Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona 08003, Spain.
15Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain
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Halit Ongen
2Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
3Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
4Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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John J. Palowitch
16Department of Statistics and Operations Research, University of North Carolina, Chapel Hill, NC, 27599, USA
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YoSon Park
17Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
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Christine B. Peterson
18Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA
19Present address: Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA
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Gerald Quon
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
20Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139, USA
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Stephan Ripke
21Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
22Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA
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Andrey A. Shabalin
23Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
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Tyler C. Shimko
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Benjamin J. Strober
11Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
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Timothy J. Sullivan
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Nicole A. Teran
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Emily K. Tsang
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Hailei Zhang
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Yi-Hui Zhou
24Bioinformatics Research Center and Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
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Alexis Battle
25Department of Computer Science, Johns Hopkins University, Baltimore, MD, 21218, USA
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Carlos D. Bustamonte
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
26Department of Statistics, Stanford University, Stanford, CA, 94305, USA
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Nancy J. Cox
9Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, 37232, USA
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Barbara E. Engelhardt
27Department of Computer Science, Center for Statistics and Machine Learning, Princeton University, Princeton, NJ, 08540, USA
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Eleazar Eskin
12Department of Human Genetics, University of California, Los Angeles, CA, 90095, USA
28Department of Computer Science, University of California, Los Angeles, CA, 90095, USA
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Gad Getz
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
29Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
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Manolis Kellis
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
20Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139, USA
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Gen Li
30Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA
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Daniel G. MacArthur
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
20Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139, USA
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Andrew B. Nobel
16Department of Statistics and Operations Research, University of North Carolina, Chapel Hill, NC, 27599, USA
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Chiara Sabbati
18Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA
26Department of Statistics, Stanford University, Stanford, CA, 94305, USA
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Xiaoquan Wen
31Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
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Fred A. Wright
24Bioinformatics Research Center and Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
32Department of Statistics, North Carolina State University, Raleigh NC, 27695, USA
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Tuuli Lappalainen
5New York Genome Center, New York, NY, 10013, USA
6Department of Systems Biology, Columbia University, New York, NY, 10032, USA
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Kristin G. Ardlie
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA
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Emmanouil T. Dermitzakis
2Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
3Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
4Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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Christopher D. Brown
17Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
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  • ORCID record for Christopher D. Brown
Stephen B. Montgomery
7Department of Genetics, Stanford University, Stanford, CA, 94305, USA
8Department of Pathology, Stanford University, Stanford, CA, 94305, USA
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Abstract

Expression quantitative trait locus (eQTL) mapping provides a powerful means to identify functional variants influencing gene expression and disease pathogenesis. We report the identification of cis-eQTLs from 7,051 post-mortem samples representing 44 tissues and 449 individuals as part of the Genotype-Tissue Expression (GTEx) project. We find a cis-eQTL for 88% of all annotated protein-coding genes, with one-third having multiple independent effects. We identify numerous tissue-specific cis-eQTLs, highlighting the unique functional impact of regulatory variation in diverse tissues. By integrating large-scale functional genomics data and state-of-the-art fine-mapping algorithms, we identify multiple features predictive of tissue-specific and shared regulatory effects. We improve estimates of cis-eQTL sharing and effect sizes using allele specific expression across tissues. Finally, we demonstrate the utility of this large compendium of cis-eQTLs for understanding the tissue-specific etiology of complex traits, including coronary artery disease. The GTEx project provides an exceptional resource that has improved our understanding of gene regulation across tissues and the role of regulatory variation in human genetic diseases.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Local genetic effects on gene expression across 44 human tissues
François Aguet, Andrew A. Brown, Stephane E. Castel, Joe R. Davis, Pejman Mohammadi, Ayellet V. Segrè, Zachary Zappala, Nathan S. Abell, Laure Frésard, Eric R. Gamazon, Ellen Gelfand, Michael J. Gloudemans, Yuan He, Farhad Hormozdiari, Xiao Li, Xin Li, Boxiang Liu, Diego Garrido-Martín, Halit Ongen, John J. Palowitch, YoSon Park, Christine B. Peterson, Gerald Quon, Stephan Ripke, Andrey A. Shabalin, Tyler C. Shimko, Benjamin J. Strober, Timothy J. Sullivan, Nicole A. Teran, Emily K. Tsang, Hailei Zhang, Yi-Hui Zhou, Alexis Battle, Carlos D. Bustamonte, Nancy J. Cox, Barbara E. Engelhardt, Eleazar Eskin, Gad Getz, Manolis Kellis, Gen Li, Daniel G. MacArthur, Andrew B. Nobel, Chiara Sabbati, Xiaoquan Wen, Fred A. Wright, GTEx Consortium, Tuuli Lappalainen, Kristin G. Ardlie, Emmanouil T. Dermitzakis, Christopher D. Brown, Stephen B. Montgomery
bioRxiv 074450; doi: https://doi.org/10.1101/074450
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Local genetic effects on gene expression across 44 human tissues
François Aguet, Andrew A. Brown, Stephane E. Castel, Joe R. Davis, Pejman Mohammadi, Ayellet V. Segrè, Zachary Zappala, Nathan S. Abell, Laure Frésard, Eric R. Gamazon, Ellen Gelfand, Michael J. Gloudemans, Yuan He, Farhad Hormozdiari, Xiao Li, Xin Li, Boxiang Liu, Diego Garrido-Martín, Halit Ongen, John J. Palowitch, YoSon Park, Christine B. Peterson, Gerald Quon, Stephan Ripke, Andrey A. Shabalin, Tyler C. Shimko, Benjamin J. Strober, Timothy J. Sullivan, Nicole A. Teran, Emily K. Tsang, Hailei Zhang, Yi-Hui Zhou, Alexis Battle, Carlos D. Bustamonte, Nancy J. Cox, Barbara E. Engelhardt, Eleazar Eskin, Gad Getz, Manolis Kellis, Gen Li, Daniel G. MacArthur, Andrew B. Nobel, Chiara Sabbati, Xiaoquan Wen, Fred A. Wright, GTEx Consortium, Tuuli Lappalainen, Kristin G. Ardlie, Emmanouil T. Dermitzakis, Christopher D. Brown, Stephen B. Montgomery
bioRxiv 074450; doi: https://doi.org/10.1101/074450

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