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Mechanisms of tissue-specific genetic regulation revealed by latent factors across eQTLs

Yuan He, Surya B. Chhetri, Marios Arvanitis, Kaushik Srinivasan, View ORCID ProfileFrançois Aguet, View ORCID ProfileKristin G. Ardlie, View ORCID ProfileAlvaro N. Barbeira, Rodrigo Bonazzola, View ORCID ProfileHae Kyung Im, GTEx Consortium, View ORCID ProfileChristopher D. Brown, View ORCID ProfileAlexis Battle
doi: https://doi.org/10.1101/785584
Yuan He
1Department of Biomedical Engineering, Johns Hopkins University, 21218 Baltimore, MD, USA
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Surya B. Chhetri
2HudsonAlpha Institute for Biotechnology, 35806 Huntsville, AL, USA
3Department of Biomedical Engineering, Johns Hopkins University, 21218 Baltimore, MD, USA
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Marios Arvanitis
1Department of Biomedical Engineering, Johns Hopkins University, 21218 Baltimore, MD, USA
4Department of Medicine, Division of Cardiology, Johns Hopkins University, 21287 Baltimore, MD, USA
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Kaushik Srinivasan
5Department of Computer Science, Johns Hopkins University, 21218 Baltimore, MD, USA
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François Aguet
6The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Kristin G. Ardlie
6The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Alvaro N. Barbeira
7Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Rodrigo Bonazzola
7Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Hae Kyung Im
7Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Christopher D. Brown
9Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 19104 Philadelphia, PA, USA
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  • For correspondence: ajbattle@jhu.edu chrbro@pennmedicine.upenn.edu
Alexis Battle
1Department of Biomedical Engineering, Johns Hopkins University, 21218 Baltimore, MD, USA
5Department of Computer Science, Johns Hopkins University, 21218 Baltimore, MD, USA
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  • For correspondence: ajbattle@jhu.edu chrbro@pennmedicine.upenn.edu
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Abstract

Background Genetic regulation of gene expression, revealed by expression quantitative trait loci (eQTLs), varies across tissues in complex patterns ranging from highly tissue-specific effects to effects shared across many or all tissues. Improved characterization of these patterns may allow us to better understand the biological mechanisms that underlie tissue-specific gene regulation and disease etiology.

Results We develop a constrained matrix factorization model to learn patterns of tissue sharing and tissue specificity of eQTLs across 49 human tissues from the Genotype-Tissue Expression (GTEx) project. The learned factors include patterns reflecting tissues with known biological similarity or shared cell types, in addition to a dense factor representing a universal genetic effect across all tissues. To explore the regulatory mechanisms that generate tissue-specific patterns of expression, we evaluate chromatin state enrichment and identify specific transcription factors with binding sites enriched for eQTLs from each factor.

Conclusions Our results demonstrate that matrix factorization can be applied to learn the tissue specificity pattern of eQTLs and that it exhibits better biological interpretability than heuristic methods. We present a framework to characterize the tissue specificity of eQTLs, and we identify examples of tissue-specific eQTLs that may be driven by tissue-specific transcription factor (TF) binding, with relevance to interpretation of disease association.

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-NC-ND 4.0 International license.
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Posted October 06, 2019.
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Mechanisms of tissue-specific genetic regulation revealed by latent factors across eQTLs
Yuan He, Surya B. Chhetri, Marios Arvanitis, Kaushik Srinivasan, François Aguet, Kristin G. Ardlie, Alvaro N. Barbeira, Rodrigo Bonazzola, Hae Kyung Im, GTEx Consortium, Christopher D. Brown, Alexis Battle
bioRxiv 785584; doi: https://doi.org/10.1101/785584
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Mechanisms of tissue-specific genetic regulation revealed by latent factors across eQTLs
Yuan He, Surya B. Chhetri, Marios Arvanitis, Kaushik Srinivasan, François Aguet, Kristin G. Ardlie, Alvaro N. Barbeira, Rodrigo Bonazzola, Hae Kyung Im, GTEx Consortium, Christopher D. Brown, Alexis Battle
bioRxiv 785584; doi: https://doi.org/10.1101/785584

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