RT Journal Article
SR Electronic
T1 Mechanisms of tissue-specific genetic regulation revealed by latent factors across eQTLs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 785584
DO 10.1101/785584
A1 Yuan He
A1 Surya B. Chhetri
A1 Marios Arvanitis
A1 Kaushik Srinivasan
A1 François Aguet
A1 Kristin G. Ardlie
A1 Alvaro N. Barbeira
A1 Rodrigo Bonazzola
A1 Hae Kyung Im
A1 GTEx Consortium
A1 Christopher D. Brown
A1 Alexis Battle
YR 2019
UL http://biorxiv.org/content/early/2019/10/06/785584.abstract
AB 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.