Multi-ancestry Genome-wide Association Study of Inpatient Opioid Dosing Following Knee or Hip Arthroplasty

Opioid analgesics are commonly prescribed to manage acute postoperative pain. However, individuals vary in their opioid dosing needs, with no validated biomarkers to guide prescribing. We used electronic health records data from the Million Veteran Program sample to investigate individual differences in opioid analgesic dosing following knee (n=18,540) or hip (n=9,363) arthroplasty in a predominantly male (93%) veteran sample. We extracted data from pharmacy records on inpatient opioid medications dispensed to estimate each patient's average daily morphine milligram equivalent (MME) doses. We used genome-wide association studies (GWAS) stratified by arthroplasty type (i.e., knee or hip) and genetically inferred ancestry group (i.e., European-like (EUR), African-like (AFR), and Admixed American-like (AMR) to identify genetic variants associated with daily MME doses. Within-ancestry summary statistics from the knee and hip arthroplasty GWAS were meta-analyzed, followed by a cross-ancestry GWAS meta-analysis. We identified two genome-wide significant loci in the AFR hip arthroplasty GWAS and three in the AMR GWAS, through no variants were genome-wide significant in the cross-ancestry meta-analysis. Genes mapped to these loci were implicated in a wide range of biological functions, including T-cell activation, chromatin organization and epigenetic regulation, epidermal differentiation and cell adhesion, and cell growth and organ development. Tissue enrichment analysis revealed significant enrichment in brain tissue from early infancy developmental stage. This study provides a proof-of-concept framework for the use of electronic health records data to examine the genetics of opioid dosing in the management of post-operative pain.