PT  - JOURNAL ARTICLE
AU  - Brian Jo
AU  - Yuan He
AU  - Benjamin J. Strober
AU  - Princy Parsana
AU  - François Aguet
AU  - Andrew A. Brown
AU  - Stephane E. Castel
AU  - Eric R. Gamazon
AU  - Ariel Gewirtz
AU  - Genna Gliner
AU  - Buhm Han
AU  - Amy Z. He
AU  - Eun Yong Kang
AU  - Ian C. McDowell
AU  - Xiao Li
AU  - Pejman Mohammadi
AU  - Christine B. Peterson
AU  - Gerald Quon
AU  - Ashis Saha
AU  - Ayellet V. Segrè
AU  - Jae Hoon Sul
AU  - Timothy J. Sullivan
AU  - Kristin G. Ardlie
AU  - Christopher D. Brown
AU  - Donald F. Conrad
AU  - Nancy J. Cox
AU  - Emmanouil T. Dermitzakis
AU  - Eleazar Eskin
AU  - Manolis Kellis
AU  - Tuuli Lappalainen
AU  - Chiara Sabatti
AU  - GTEx Consortium
AU  - Barbara E. Engelhardt
AU  - Alexis Battle
TI  - Distant regulatory effects of genetic variation in multiple human tissues
AID  - 10.1101/074419
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 074419
4099  - http://biorxiv.org/content/early/2016/09/09/074419.short
4100  - http://biorxiv.org/content/early/2016/09/09/074419.full
AB  - Understanding the genetics of gene regulation provides information on the cellular mechanisms through which genetic variation influences complex traits. Expression quantitative trait loci, or eQTLs, are enriched for polymorphisms that have been found to be associated with disease risk. While most analyses of human data has focused on regulation of expression by nearby variants (cis-eQTLs), distal or trans-eQTLs may have broader effects on the transcriptome and important phenotypic consequences, necessitating a comprehensive study of the effects of genetic variants on distal gene transcription levels. In this work, we identify trans-eQTLs in the Genotype Tissue Expression (GTEx) project data1, consisting of 449 individuals with RNA-sequencing data across 44 tissue types. We find 81 genes with a trans-eQTL in at least one tissue, and we demonstrate that trans-eQTLs are more likely than cis-eQTLs to have effects specific to a single tissue. We evaluate the genomic and functional properties of trans-eQTL variants, identifying strong enrichment in enhancer elements and Piwi-interacting RNA clusters. Finally, we describe three tissue-specific regulatory loci underlying relevant disease associations: 9q22 in thyroid that has a role in thyroid cancer, 5q31 in skeletal muscle, and a previously reported master regulator near KLF14 in adipose. These analyses provide a comprehensive characterization of trans-eQTLs across human tissues, which contribute to an improved understanding of the tissue-specific cellular mechanisms of regulatory genetic variation.