The impact of rare variation on gene expression across tissues.

Nature
Authors
Keywords
Abstract

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

Year of Publication
2017
Journal
Nature
Volume
550
Issue
7675
Pages
239-243
Date Published
2017 10 11
ISSN
1476-4687
DOI
10.1038/nature24267
PubMed ID
29022581
PubMed Central ID
PMC5877409
Links
Grant list
1R01MH109905-01 / NH / NIH HHS / United States
T32 GM007057 / GM / NIGMS NIH HHS / United States
T32 CA096520 / CA / NCI NIH HHS / United States
R01 DA006227 / DA / NIDA NIH HHS / United States
R01 HG008150 / HG / NHGRI NIH HHS / United States
U01 HG007610 / HG / NHGRI NIH HHS / United States
R01 MH109905 / MH / NIMH NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
T32 HG000044 / HG / NHGRI NIH HHS / United States
U01 HG007436 / HG / NHGRI NIH HHS / United States
R01 HG008150 / NH / NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States
R01 GM120167 / GM / NIGMS NIH HHS / United States