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Exploiting the GTEx resources to decipher the mechanisms at GWAS loci

View ORCID ProfileAlvaro N Barbeira, Rodrigo Bonazzola, View ORCID ProfileEric R Gamazon, View ORCID ProfileYanyu Liang, View ORCID ProfileYoSon Park, View ORCID ProfileSarah Kim-Hellmuth, View ORCID ProfileGao Wang, Zhuoxun Jiang, Dan Zhou, View ORCID ProfileFarhad Hormozdiari, Boxiang Liu, Abhiram Rao, View ORCID ProfileAndrew R Hamel, View ORCID ProfileMilton D Pividori, View ORCID ProfileFrançois Aguet, GTEx GWAS Working Group, View ORCID ProfileLisa Bastarache, View ORCID ProfileDaniel M Jordan, Marie Verbanck, View ORCID ProfileRon Do, GTEx Consortium, View ORCID ProfileMatthew Stephens, Kristin Ardlie, Mark McCarthy, View ORCID ProfileStephen B Montgomery, View ORCID ProfileAyellet V Segrè, View ORCID ProfileChristopher D. Brown, View ORCID ProfileTuuli Lappalainen, View ORCID ProfileXiaoquan Wen, View ORCID ProfileHae Kyung Im
doi: https://doi.org/10.1101/814350
Alvaro N Barbeira
1Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Rodrigo Bonazzola
1Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Eric R Gamazon
2Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
3Data Science Institute, Vanderbilt University, Nashville, TN, USA
4Clare Hall, University of Cambridge, Cambridge, UK
5MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Yanyu Liang
1Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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YoSon Park
6Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
7Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
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Sarah Kim-Hellmuth
8Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany
9New York Genome Center, New York, NY, USA
10Department of Systems Biology, Columbia University, New York, NY, USA
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Gao Wang
11Department of Human Genetics, University of Chicago, Chicago, IL, USA
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Zhuoxun Jiang
1Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Dan Zhou
2Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Farhad Hormozdiari
12The Broad Institute of MIT and Harvard, Cambridge, MA, USA
13Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Boxiang Liu
14Department of Biology, Stanford University, Stanford, California 94305, USA
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Abhiram Rao
14Department of Biology, Stanford University, Stanford, California 94305, USA
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Andrew R Hamel
12The Broad Institute of MIT and Harvard, Cambridge, MA, USA
15Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
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Milton D Pividori
1Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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  • ORCID record for Milton D Pividori
François Aguet
12The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Lisa Bastarache
16Department of Biomedical Informatics, Department of Medicine, Vanderbilt University, Nashville, TN, USA
17Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
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Daniel M Jordan
18Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
19Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
20The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount sinai, New York, New York, USA
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Marie Verbanck
18Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
19Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
20The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount sinai, New York, New York, USA
21Université de Paris - EA 7537 BIOSTM, France
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Ron Do
18Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
19Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
20The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount sinai, New York, New York, USA
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Matthew Stephens
11Department of Human Genetics, University of Chicago, Chicago, IL, USA
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Kristin Ardlie
12The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Mark McCarthy
22University of Oxford, United Kingdom
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Stephen B Montgomery
23Department of Genetics, Stanford University, Stanford, CA, USA
24Department of Pathology, Stanford University, Stanford, CA, USA
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Ayellet V Segrè
12The Broad Institute of MIT and Harvard, Cambridge, MA, USA
15Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
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Christopher D. Brown
6Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
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Tuuli Lappalainen
9New York Genome Center, New York, NY, USA
10Department of Systems Biology, Columbia University, New York, NY, USA
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Xiaoquan Wen
25Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
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Hae Kyung Im
1Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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  • For correspondence: haky@uchicago.edu
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Abstract

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.

Competing Interest Statement

Details of competing interests are listed on the manuscript.

Footnotes

  • We changed the title to better reflect the content of the paper and restructured the text and streamlined the supplemental data.

  • https://github.com/hakyimlab/gtex-gwas-analysis

Copyright 
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 4.0 International license.
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Posted May 23, 2020.
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Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
Alvaro N Barbeira, Rodrigo Bonazzola, Eric R Gamazon, Yanyu Liang, YoSon Park, Sarah Kim-Hellmuth, Gao Wang, Zhuoxun Jiang, Dan Zhou, Farhad Hormozdiari, Boxiang Liu, Abhiram Rao, Andrew R Hamel, Milton D Pividori, François Aguet, GTEx GWAS Working Group, Lisa Bastarache, Daniel M Jordan, Marie Verbanck, Ron Do, GTEx Consortium, Matthew Stephens, Kristin Ardlie, Mark McCarthy, Stephen B Montgomery, Ayellet V Segrè, Christopher D. Brown, Tuuli Lappalainen, Xiaoquan Wen, Hae Kyung Im
bioRxiv 814350; doi: https://doi.org/10.1101/814350
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Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
Alvaro N Barbeira, Rodrigo Bonazzola, Eric R Gamazon, Yanyu Liang, YoSon Park, Sarah Kim-Hellmuth, Gao Wang, Zhuoxun Jiang, Dan Zhou, Farhad Hormozdiari, Boxiang Liu, Abhiram Rao, Andrew R Hamel, Milton D Pividori, François Aguet, GTEx GWAS Working Group, Lisa Bastarache, Daniel M Jordan, Marie Verbanck, Ron Do, GTEx Consortium, Matthew Stephens, Kristin Ardlie, Mark McCarthy, Stephen B Montgomery, Ayellet V Segrè, Christopher D. Brown, Tuuli Lappalainen, Xiaoquan Wen, Hae Kyung Im
bioRxiv 814350; doi: https://doi.org/10.1101/814350

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