High-throughput framework for genetic analyses of adverse drug reactions using electronic health records

Abstract

Understanding the contribution of genetic variation to drug response can improve the delivery of precision medicine. However, genome-wide association studies (GWAS) for drug response are uncommon and are often hindered by small sample sizes. We present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions (ADRs) using "drug allergy" labels from electronic health records (EHRs). As a proof-of-concept, we conducted GWAS for ADRs to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Center's BioVU DNA Biobank. We identified 7 genetic loci associated with ADRs at P < 5 × 10-8, including known genetic associations such as CYP2D6 and OPRM1 for CYP2D6-metabolized opioid ADR. Additional expression quantitative trait loci and phenome-wide association analyses added evidence to the observed associations. Our high-throughput framework is both scalable and portable, enabling impactful pharmacogenomic research to improve precision medicine.

Fig 1

A) Manhattan plots of genome-wide association studies (GWAS) for codeine (left) and CYP2D6-metabolized opioid (right) adverse drug reactions (ADRs). Red lines on Manhattan plots show the genome-wide significance level (P < 5.0 × 10⁻⁸). B) CYP2D6 locus for CYP2D6-metabolized opioid ADRs. SNPs are colored according to their linkage disequilibrium (LD, based on 1000 Genome phase3 EUR reference panel) with the lead variant rs739296 (22:42389948), which is marked with a purple diamond. The lead variant rs9620007 (22:42405657) for codeine ADRs is also labeled. Dotted gray line shows the genome-wide significance level (P < 5.0 × 10⁻⁸).

Fig 2

Risk loci for meperidine (a) and penicillin (b) adverse drug reactions (ADRs). SNPs are colored according to their linkage disequilibrium (LD, based on 1000 Genome phase3 EUR reference panel) with the lead variants rs11049274 (12:28161055) for meperidine ADRs and rs115200108 (6:31327622) for penicillin ADRs, which are marked with a purple diamond. Dotted gray line shows the genome-wide significance level (P < 5.0 × 10⁻⁸).