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Diverse transcriptomic signatures across human tissues identify functional rare genetic variation

View ORCID ProfileNicole M. Ferraro, View ORCID ProfileBenjamin J. Strober, View ORCID ProfileJonah Einson, Xin Li, View ORCID ProfileFrancois Aguet, View ORCID ProfileAlvaro N. Barbeira, View ORCID ProfileStephane E. Castel, View ORCID ProfileJoe R. Davis, View ORCID ProfileAustin T. Hilliard, Bence Kotis, View ORCID ProfileYoSon Park, Alexandra J. Scott, Craig Smail, Emily K. Tsang, View ORCID ProfileKristin G. Ardlie, Themistocles L. Assimes, Ira Hall, View ORCID ProfileHae Kyung Im, GTEx Consortium, View ORCID ProfileTuuli Lappalainen, View ORCID ProfilePejman Mohammadi, View ORCID ProfileStephen B. Montgomery, View ORCID ProfileAlexis Battle
doi: https://doi.org/10.1101/786053
Nicole M. Ferraro
1Biomedical Informatics Training Program, Stanford University, Stanford, CA
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Benjamin J. Strober
2Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD
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  • ORCID record for Benjamin J. Strober
Jonah Einson
3Department of Biomedical Informatics, Columbia University, New York, NY
4New York Genome Center, New York, NY
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Xin Li
5Department of Pathology, Stanford University, Stanford, CA
6Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, China
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Francois Aguet
7The Broad Institute of MIT and Harvard, Cambridge, MA
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Alvaro N. Barbeira
8Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL
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Stephane E. Castel
9Department of Systems Biology, Columbia University, New York, NY
10New York Genome Center, New York, NY
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Joe R. Davis
5Department of Pathology, Stanford University, Stanford, CA
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Austin T. Hilliard
11Palo Alto Veterans Institute for Research, Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA
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Bence Kotis
12Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
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YoSon Park
13Department of Systems Pharmacology and Translational Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
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Alexandra J. Scott
14McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO
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Craig Smail
1Biomedical Informatics Training Program, Stanford University, Stanford, CA
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Emily K. Tsang
5Department of Pathology, Stanford University, Stanford, CA
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Kristin G. Ardlie
7The Broad Institute of MIT and Harvard, Cambridge, MA
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Themistocles L. Assimes
11Palo Alto Veterans Institute for Research, Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA
15Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Ira Hall
14McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO
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Hae Kyung Im
6Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, China
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Tuuli Lappalainen
9Department of Systems Biology, Columbia University, New York, NY
10New York Genome Center, New York, NY
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Pejman Mohammadi
10New York Genome Center, New York, NY
12Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
16Scripps Translational Science Institute, La Jolla, CA
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  • For correspondence: pejman@scripps.edu smontgom@stanford.edu ajbattle@jhu.edu
Stephen B. Montgomery
5Department of Pathology, Stanford University, Stanford, CA
17Department of Genetics, Stanford University, Stanford, CA
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  • For correspondence: pejman@scripps.edu smontgom@stanford.edu ajbattle@jhu.edu
Alexis Battle
2Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD
18Department of Computer Science, Johns Hopkins University, Baltimore, MD
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  • For correspondence: pejman@scripps.edu smontgom@stanford.edu ajbattle@jhu.edu
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Abstract

Rare genetic variation is abundant in the human genome, yet identifying functional rare variants and their impact on traits remains challenging. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants. Here, we expand detection of genetically driven transcriptome abnormalities by evaluating and integrating gene expression, allele-specific expression, and alternative splicing from multi-tissue RNA-sequencing data. We demonstrate that each signal informs unique classes of rare variants. We further develop Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function. Assessing rare variants prioritized by Watershed in the UK Biobank and Million Veterans Program, we identify large effects across 34 traits, and 33 rare variant-trait combinations with both high Watershed scores and large trait effect sizes. Together, we provide a comprehensive analysis of the transcriptomic impact of rare variation and a framework to prioritize functional rare variants and assess their trait relevance.

One-sentence summary Integrating expression, allelic expression and splicing across tissues identifies rare variants with relevance to traits.

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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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Posted October 03, 2019.
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Diverse transcriptomic signatures across human tissues identify functional rare genetic variation
Nicole M. Ferraro, Benjamin J. Strober, Jonah Einson, Xin Li, Francois Aguet, Alvaro N. Barbeira, Stephane E. Castel, Joe R. Davis, Austin T. Hilliard, Bence Kotis, YoSon Park, Alexandra J. Scott, Craig Smail, Emily K. Tsang, Kristin G. Ardlie, Themistocles L. Assimes, Ira Hall, Hae Kyung Im, GTEx Consortium, Tuuli Lappalainen, Pejman Mohammadi, Stephen B. Montgomery, Alexis Battle
bioRxiv 786053; doi: https://doi.org/10.1101/786053
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Diverse transcriptomic signatures across human tissues identify functional rare genetic variation
Nicole M. Ferraro, Benjamin J. Strober, Jonah Einson, Xin Li, Francois Aguet, Alvaro N. Barbeira, Stephane E. Castel, Joe R. Davis, Austin T. Hilliard, Bence Kotis, YoSon Park, Alexandra J. Scott, Craig Smail, Emily K. Tsang, Kristin G. Ardlie, Themistocles L. Assimes, Ira Hall, Hae Kyung Im, GTEx Consortium, Tuuli Lappalainen, Pejman Mohammadi, Stephen B. Montgomery, Alexis Battle
bioRxiv 786053; doi: https://doi.org/10.1101/786053

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