Distant regulatory effects of genetic variation in multiple human tissues 1

40 Understanding the genetics of gene regulation provides information on the cellular mechanisms 41 through which genetic variation influences complex traits. Expression quantitative trait loci, or 42 eQTLs, are enriched for polymorphisms that have been found to be associated with disease risk. 43 While most analyses of human data has focused on regulation of expression by nearby variants 44 (cis-eQTLs), distal or trans-eQTLs may have broader effects on the transcriptome and important 45 phenotypic consequences, necessitating a comprehensive study of the effects of genetic variants 46 on distal gene transcription levels. In this work, we identify trans-eQTLs in the Genotype Tissue 47 Expression (GTEx) project data, consisting of 449 individuals with RNA-sequencing data 48 across 44 tissue types. We find 81 genes with a trans-eQTL in at least one tissue, and we 49 demonstrate that trans-eQTLs are more likely than cis-eQTLs to have effects specific to a single 50 tissue. We evaluate the genomic and functional properties of trans-eQTL variants, identifying 51 strong enrichment in enhancer elements and Piwi-interacting RNA clusters. Finally, we describe 52 three tissue-specific regulatory loci underlying relevant disease associations: 9q22 in thyroid that 53 has a role in thyroid cancer, 5q31 in skeletal muscle, and a previously reported master regulator 54 near KLF14 in adipose. These analyses provide a comprehensive characterization of trans-eQTLs 55 across human tissues, which contribute to an improved understanding of the tissue-specific 56 cellular mechanisms of regulatory genetic variation. 57 Introduction 58 Variation in the human genome influences complex disease risk through changes at a cellular 59 level. Many disease-associated variants are also associated with gene expression levels through 60 which they mediate disease risk. The majority of expression quantitative trait locus (eQTL) 61 studies thus far have focused on localor cis-eQTLs because of the relative simplicity of 62 association mapping in human for both statistical and biological reasons. Trans-eQTLs, or 63 genetic variants that affect gene expression levels of distant target genes, have received much 64 less attention in comparison to cis-eQTLs, in part due to the considerable multiple hypotheses 65 testing burden. Far fewer replicable, strong effect trans-eQTLs have been discovered in human 66 data as compared to cis-eQTLs, unlike in model organisms such as Saccharomyces cerevisiae or 67 Arabidopsis thaliana. However, a handful of replicable trans-eQTLs have now been 68 identified in human tissues. Additionally, recent work has suggested that trans-eQTLs 69 contribute substantially to the genetic regulation of complex diseases, motivating a careful 70 examination of the role of trans-eQTLs across human tissues in disease etiology. 71 Here, we identify trans-eQTLs in the Genotype-Tissue Expression (GTEx) v6 data, which 72 include 449 individuals with imputed genotypes and RNA-seq data across 44 tissues for a total 73 of 7,051 samples. We evaluate the tissue-specificity of trans-eQTLs, and we demonstrate 74 replication of trans-eQTLs in a large independent RNA-seq study. We show enrichment of 75 trans-eQTLs for tests restricted to genetic variants associated with expression of nearby genes 76 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi. org/10.1101/074419 doi: bioRxiv preprint first posted online Sep. 9, 2016;