The impact of rare variation on gene expression across tissues

Abstract

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk 1,2,3,4 . While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants 1,5 . Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles 1,6,7 , 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 8,9,10,11 , 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 12 . 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.

Cited by papers we hold 14

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• Detection of aberrant splicing events in RNA-seq data using FRASER · 2021
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• CADD-Splice—improving genome-wide variant effect prediction using deep learning-derived splice scores · 2021
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• Rare variant contribution to human disease in 281,104 UK Biobank exomes · 2021
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• A vast resource of allelic expression data spanning human tissues · 2020
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• DESE: estimating driver tissues by selective expression of genes associated with complex diseases or traits · 2019
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• Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution · 2019
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• Genetic effects on gene expression across human tissues · 2017
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• Genetic diagnosis of Mendelian disorders via RNA sequencing · 2017
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• Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations · 2017
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