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

• Main Authors: Jihye Park, Soo Youn Lee, Su Youn Baik, Chan Hee Park, Jun Hee Yoon, Brian Y. Ryu, Ju Han Kim
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: International Journal of Molecular Sciences
• Subjects: drug response; genetic variability; deleterious sequence variant; pharmacogenomics; pharmacogenetics; next generation sequencing
• Online Access: https://www.mdpi.com/1422-0067/21/9/3091
• ISSN: 1661-6596; 1422-0067

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.