Tissue-specific genetic features inform prediction of drug side effects in clinical trials.
Sci Adv
; 6(37)2020 09.
Article
in En
| MEDLINE
| ID: mdl-32917698
ABSTRACT
Adverse side effects often account for the failure of drug clinical trials. We evaluated whether a phenome-wide association study (PheWAS) of 1167 phenotypes in >360,000 U.K. Biobank individuals, in combination with gene expression and expression quantitative trait loci (eQTL) in 48 tissues, can inform prediction of drug side effects in clinical trials. We determined that drug target genes with five genetic features-tissue specificity of gene expression, Mendelian associations, phenotype- and tissue-level effects of genome-wide association (GWA) loci driven by eQTL, and genetic constraint-confer a 2.6-fold greater risk of side effects, compared to genes without such features. The presence of eQTL in multiple tissues resulted in more unique phenotypes driven by GWA loci, suggesting that drugs delivered to multiple tissues can induce several side effects. We demonstrate the utility of PheWAS and eQTL data from multiple tissues for informing drug side effect prediction and highlight the need for tissue-specific drug delivery.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug-Related Side Effects and Adverse Reactions
/
Genome-Wide Association Study
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Sci Adv
Year:
2020
Document type:
Article
Affiliation country:
Estados Unidos