The impact of rare variation on gene expression across tissues
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 dis...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2017
|
| _version_ | 1797087142286983168 |
|---|---|
| author | Li, X Kim, Y Tsang, EK Davis, JR Damani, FN Chiang, C Hess, GT Zappala, Z Strober, BJ Scott, AJ Li, A Ganna, A Bassik, MC Merker, JD Hall, IM Battle, A Montgomery, SB McCarthy, MI Payne, AJ |
| author_facet | Li, X Kim, Y Tsang, EK Davis, JR Damani, FN Chiang, C Hess, GT Zappala, Z Strober, BJ Scott, AJ Li, A Ganna, A Bassik, MC Merker, JD Hall, IM Battle, A Montgomery, SB McCarthy, MI Payne, AJ |
| author_sort | Li, X |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:31:48Z |
| format | Journal article |
| id | oxford-uuid:a77c7e25-e5e8-40c8-af26-a1270cb0e5a0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:31:48Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:a77c7e25-e5e8-40c8-af26-a1270cb0e5a02022-03-27T02:55:03ZThe impact of rare variation on gene expression across tissuesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a77c7e25-e5e8-40c8-af26-a1270cb0e5a0EnglishSymplectic Elements at OxfordNature Publishing Group2017Li, XKim, YTsang, EKDavis, JRDamani, FNChiang, CHess, GTZappala, ZStrober, BJScott, AJLi, AGanna, ABassik, MCMerker, JDHall, IMBattle, AMontgomery, SBMcCarthy, MIPayne, AJRare 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. |
| spellingShingle | Li, X Kim, Y Tsang, EK Davis, JR Damani, FN Chiang, C Hess, GT Zappala, Z Strober, BJ Scott, AJ Li, A Ganna, A Bassik, MC Merker, JD Hall, IM Battle, A Montgomery, SB McCarthy, MI Payne, AJ The impact of rare variation on gene expression across tissues |
| title | The impact of rare variation on gene expression across tissues |
| title_full | The impact of rare variation on gene expression across tissues |
| title_fullStr | The impact of rare variation on gene expression across tissues |
| title_full_unstemmed | The impact of rare variation on gene expression across tissues |
| title_short | The impact of rare variation on gene expression across tissues |
| title_sort | impact of rare variation on gene expression across tissues |
| work_keys_str_mv | AT lix theimpactofrarevariationongeneexpressionacrosstissues AT kimy theimpactofrarevariationongeneexpressionacrosstissues AT tsangek theimpactofrarevariationongeneexpressionacrosstissues AT davisjr theimpactofrarevariationongeneexpressionacrosstissues AT damanifn theimpactofrarevariationongeneexpressionacrosstissues AT chiangc theimpactofrarevariationongeneexpressionacrosstissues AT hessgt theimpactofrarevariationongeneexpressionacrosstissues AT zappalaz theimpactofrarevariationongeneexpressionacrosstissues AT stroberbj theimpactofrarevariationongeneexpressionacrosstissues AT scottaj theimpactofrarevariationongeneexpressionacrosstissues AT lia theimpactofrarevariationongeneexpressionacrosstissues AT gannaa theimpactofrarevariationongeneexpressionacrosstissues AT bassikmc theimpactofrarevariationongeneexpressionacrosstissues AT merkerjd theimpactofrarevariationongeneexpressionacrosstissues AT hallim theimpactofrarevariationongeneexpressionacrosstissues AT battlea theimpactofrarevariationongeneexpressionacrosstissues AT montgomerysb theimpactofrarevariationongeneexpressionacrosstissues AT mccarthymi theimpactofrarevariationongeneexpressionacrosstissues AT payneaj theimpactofrarevariationongeneexpressionacrosstissues AT lix impactofrarevariationongeneexpressionacrosstissues AT kimy impactofrarevariationongeneexpressionacrosstissues AT tsangek impactofrarevariationongeneexpressionacrosstissues AT davisjr impactofrarevariationongeneexpressionacrosstissues AT damanifn impactofrarevariationongeneexpressionacrosstissues AT chiangc impactofrarevariationongeneexpressionacrosstissues AT hessgt impactofrarevariationongeneexpressionacrosstissues AT zappalaz impactofrarevariationongeneexpressionacrosstissues AT stroberbj impactofrarevariationongeneexpressionacrosstissues AT scottaj impactofrarevariationongeneexpressionacrosstissues AT lia impactofrarevariationongeneexpressionacrosstissues AT gannaa impactofrarevariationongeneexpressionacrosstissues AT bassikmc impactofrarevariationongeneexpressionacrosstissues AT merkerjd impactofrarevariationongeneexpressionacrosstissues AT hallim impactofrarevariationongeneexpressionacrosstissues AT battlea impactofrarevariationongeneexpressionacrosstissues AT montgomerysb impactofrarevariationongeneexpressionacrosstissues AT mccarthymi impactofrarevariationongeneexpressionacrosstissues AT payneaj impactofrarevariationongeneexpressionacrosstissues |