Multi-ancestry genome-wide association meta-analysis of buprenorphine treatment response

Although the mu-opioid partial agonist buprenorphine is increasingly being prescribed to treat opioid use disorder, patients' responses to the drug vary and few clinical and no genetic predictors of treatment response have been identified. We conducted a genome-wide association study (GWAS) meta-analysis of buprenorphine treatment response (defined using urine drug screen results) in 4394 Veterans with opioid use disorder from the VA Million Veteran Program (751 of African-like ancestry [AFR] and 3643 of European-like ancestry [EUR]) and 296 participants from a clinical trial of extended-release buprenorphine (n_AFR = 104, n_EUR = 192). We conducted within-ancestry GWAS in both cohorts, followed by cross-ancestry, fixed-effects GWAS meta-analyses within and across cohorts. We also examined associations between demographic and clinical characteristics and buprenorphine treatment response. The cross-ancestry meta-analysis of both cohorts identified one genome-wide significant locus (rs149319538) that maps to SLC39A10, a gene that encodes a zinc transporter. Phenome-wide association analyses of the lead variant implicated connectivity of the uncinate fasciculus, a limbic white matter fiber tract. Of the clinical characteristics, only the presence of chronic pain and a lower maximum buprenorphine dosage were related to higher odds of treatment response in adjusted models. We report here the first genome-wide significant variant associated with buprenorphine treatment response. Larger samples are needed to replicate these findings and identify additional clinical and genetic factors that predict buprenorphine treatment efficacy to enable the use of a precision approach to OUD treatment.