Clinical and Therapeutic Applications of Individual-level Tissue-Specific Imputed Transcriptomes
Wang, X.; Selvaggi, C.; Weng, L.-C.; Jurgens, S. J.; Choi, S. H.; Jha, A.; Cao, T.; Koyama, S.; Ramo, J.; Kany, S.; Ellinor, P. T.; Foulkes, A.; Lubitz, S.
Show abstract
Gene expression causally contributes to phenotypic variability. However, since tissue-specific gene expression is difficult to measure at scale, inferring phenotypic risk for individuals using expression profiles can be difficult. We statistically imputed tissue-specific gene expression for 486,452 UK Biobank participants and demonstrated its applications using rich phenotypic data in the biorepository. We performed joint analysis of transcriptome-wide association studies (TWAS) and colocalization for six traits to prioritize tissue-gene pairs for therapeutics development. Using genes identified in TWAS, we constructed imputed transcriptome risk scores and showed their predictive utility even when conditioning on genome-wide polygenic risk scores. A phenome-wide association analysis for established therapeutic targets in whole blood recapitulated known biology and prioritized repurposing potentials supported by previous literature. Our study provides evidence supporting the utility of individual-level imputed transcriptomes for discovering novel gene-tissue-phenotype trios, expression-based phenotypic risk prediction, and identifying individuals with therapeutically targetable predisposition to disease.
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