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

By Yuan He, Surya B. Chhetri, Marios Arvanitis, Kaushik Srinivasan, Fran├žois Aguet, Kristin Ardlie, Alvaro N Barbeira, Rodrigo Bonazzola, Hae Kyung Im, GTEx Consortium, Christopher D. Brown, Alexis Battle

Posted 06 Oct 2019
bioRxiv DOI: 10.1101/785584

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. Keywords: Matrix factorization, Universal eQTLs, Tissue-specific eQTLs, Transcription factors

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