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The impact of rare variation on gene expression across tissues

Xin Li, Yungil Kim, Emily K. Tsang, Joe R. Davis, Farhan N. Damani, Colby Chiang, Zachary Zappala, Benjamin J. Strober, Alexandra J. Scott, Andrea Ganna, Jason Merker, GTEx Consortium, Ira M. Hall, View ORCID ProfileAlexis Battle, Stephen B. Montgomery
doi: https://doi.org/10.1101/074443
Xin Li
1Department of Pathology, Stanford University, Stanford, CA.
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Yungil Kim
2Department of Computer Science, Johns Hopkins University, Baltimore, MD.
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Emily K. Tsang
3Biomedical Informatics Program, Stanford University, Stanford, CA.
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Joe R. Davis
4Department of Genetics, Stanford University, Stanford, CA.
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Farhan N. Damani
2Department of Computer Science, Johns Hopkins University, Baltimore, MD.
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Colby Chiang
5McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO.
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Zachary Zappala
4Department of Genetics, Stanford University, Stanford, CA.
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Benjamin J. Strober
6Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD.
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Alexandra J. Scott
5McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO.
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Andrea Ganna
7Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
8Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
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Jason Merker
1Department of Pathology, Stanford University, Stanford, CA.
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Ira M. Hall
5McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO.
10Department of Medicine, Washington University School of Medicine, St. Louis, MO.
11Department of Genetics, Washington University School of Medicine, St. Louis, MO.
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Alexis Battle
2Department of Computer Science, Johns Hopkins University, Baltimore, MD.
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  • ORCID record for Alexis Battle
  • For correspondence: ajbattle@cs.jhu.edu smontgom@stanford.edu
Stephen B. Montgomery
1Department of Pathology, Stanford University, Stanford, CA.
4Department of Genetics, Stanford University, Stanford, CA.
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  • For correspondence: ajbattle@cs.jhu.edu smontgom@stanford.edu
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Abstract

Rare genetic variants are abundant in humans yet their functional effects are often unknown and challenging to predict. The Genotype-Tissue Expression (GTEx) project provides a unique opportunity to identify the functional impact of rare variants through combined analyses of whole genomes and multi-tissue RNA-sequencing data. Here, we identify gene expression outliers, or individuals with extreme expression levels, across 44 human tissues, and characterize the contribution of rare variation to these large changes in expression. We find 58% of underexpression and 28% of overexpression outliers have underlying rare variants compared with 9% of non-outliers. Large expression effects are enriched for proximal loss-of-function, splicing, and structural variants, particularly variants near the TSS and at evolutionarily conserved sites. Known disease genes have expression outliers, underscoring that rare variants can contribute to genetic disease risk. To prioritize functional rare regulatory variants, we develop RIVER, a Bayesian approach that integrates RNA and whole genome sequencing data from the same individual. RIVER predicts functional variants significantly better than models using genomic annotations alone, and is an extensible tool for personal genome interpretation. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues with potential health consequences, and provide an integrative method for interpreting rare variants in individual genomes.

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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 September 09, 2016.
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The impact of rare variation on gene expression across tissues
Xin Li, Yungil Kim, Emily K. Tsang, Joe R. Davis, Farhan N. Damani, Colby Chiang, Zachary Zappala, Benjamin J. Strober, Alexandra J. Scott, Andrea Ganna, Jason Merker, GTEx Consortium, Ira M. Hall, Alexis Battle, Stephen B. Montgomery
bioRxiv 074443; doi: https://doi.org/10.1101/074443
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The impact of rare variation on gene expression across tissues
Xin Li, Yungil Kim, Emily K. Tsang, Joe R. Davis, Farhan N. Damani, Colby Chiang, Zachary Zappala, Benjamin J. Strober, Alexandra J. Scott, Andrea Ganna, Jason Merker, GTEx Consortium, Ira M. Hall, Alexis Battle, Stephen B. Montgomery
bioRxiv 074443; doi: https://doi.org/10.1101/074443

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