Gene-Wise Burden of Coding Variants Correlates to Noncoding Pharmacogenetic Risk Variants

International Journal of Molecular Sciences

卷:21

ChanHee Park¹  SuYoun Baik¹  SooYoun Lee¹  BrianY. Ryu¹  JuHan Kim¹  Jihye Park¹  JunHee Yoon¹ 

[1] Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 03080, Korea;

关键词: drug response;    genetic variability;    deleterious sequence variant;    pharmacogenomics;    pharmacogenetics;    next generation sequencing;   

DOI  :  10.3390/ijms21093091

来源: DOAJ

【 摘 要 】

Genetic variability can modulate individual drug responses. A significant portion of pharmacogenetic variants reside in the noncoding genome yet it is unclear if the noncoding variants directly influence protein function and expression or are present on a haplotype including a functionally relevant genetic variation (synthetic association). Gene-wise variant burden (GVB) is a gene-level measure of deleteriousness, reflecting the cumulative effects of deleterious coding variants, predicted in silico. To test potential associations between noncoding and coding pharmacogenetic variants, we computed a drug-level GVB for 5099 drugs from DrugBank for 2504 genomes of the 1000 Genomes Project and evaluated the correlation between the long-known noncoding variant-drug associations in PharmGKB, with functionally relevant rare and common coding variants aggregated into GVBs. We obtained the area under the receiver operating characteristics curve (AUC) by comparing the drug-level GVB ranks against the corresponding pharmacogenetic variants-drug associations in PharmGKB. We obtained high overall AUCs (0.710 ± 0.022–0.734 ± 0.018) for six different methods (i.e., SIFT, MutationTaster, Polyphen-2 HVAR, Polyphen-2 HDIV, phyloP, and GERP⁺⁺), and further improved the ethnicity-specific validations (0.759 ± 0.066–0.791 ± 0.078). These results suggest that a significant portion of the long-known noncoding variant-drug associations can be explained as synthetic associations with rare and common coding variants burden of the corresponding pharmacogenes.

【 授权许可】

Unknown