RT Journal Article
SR Electronic
T1 The impact of structural variation on human gene expression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 055962
DO 10.1101/055962
A1 Colby Chiang
A1 Alexandra J. Scott
A1 Joe R. Davis
A1 Emily K. Tsang
A1 Xin Li
A1 Yungil Kim
A1 Farhan N. Damani
A1 Liron Ganel
A1 GTEx Consortium
A1 Stephen B. Montgomery
A1 Alexis Battle
A1 Donald F. Conrad
A1 Ira M. Hall
YR 2016
UL http://biorxiv.org/content/early/2016/06/09/055962.abstract
AB Structural variants (SVs) are an important source of human genetic diversity but their contribution to traits, disease, and gene regulation remains unclear. The Genotype-Tissue Expression (GTEx) project presents an unprecedented opportunity to address this question due to the availability of deep whole genome sequencing (WGS) and multi-tissue RNA-seq data from 147 individuals. We used comprehensive methods to identify 24,157 high confidence SVs, and mapped cis expression quantitative trait loci (eQTLs) in 13 tissues via joint analysis of SVs, single nucleotide (SNV) and short insertion/deletion (indel) variants. We identified 24,801 eQTLs affecting the expression of 10,101 distinct genes. Based on haplotype structure and heritability partitioning, we estimate that SVs are the causal variant at 3.3-7.0% of eQTLs, which is nearly an order of magnitude higher than prior estimates from low coverage WGS and represents a 26- to 54-fold enrichment relative to their scarcity in the genome. Expression-altering SVs also have significantly larger effect sizes than SNVs and indels. We identified 787 putatively causal SVs predicted to directly alter gene expression, most of which (88.3%) are noncoding variants that show significant enrichment at enhancers and other regulatory elements. By evaluating linkage disequilibrium between SVs, SNVs and indels, we nominate 49 SVs as plausible causal variants at published genome-wide association study (GWAS) loci. Remarkably, 29.9% of the common SV-eQTLs are not well tagged by flanking SNVs, and we observe a notable abundance (relative to SNVs and indels) of rare, high impact SVs associated with aberrant expression of nearby genes. These results suggest that comprehensive WGS-based SV analyses will increase the power of both common and rare variant association studies.