Genetic loci associated with cocaine use identified using a novel approach to detect epistasis

Background Cocaine use disorder (CUD) is estimated to be 50% heritable, yet few genetic variants have been robustly associated with risk. During January 2021 to June 2024, cocaine was involved in 30% of U.S. overdose deaths. Identifying genetic contributors to CUD could inform diagnostics and treatments. The missing heritability may stem from small sample sizes, models that inadequately account for small-effect common variants, and the exclusion of large-effect structural variants like copy number changes. Epistasis likely contributes but remains challenging to detect genome-wide. Results We focused on epistasis and haplotypes rather than individual SNPs by applying the custom correlation coefficient in BlocBuster to construct allele networks from eQTL SNPs. Testing these regulatory haplotype networks for association with cocaine use in 7,826 individuals with opioid use disorder identified 12 significant associations across two ancestries. For one haplotype, raw genotyping array intensity data revealed a copy number increase at the CYP2D6 locus in individuals of European ancestry. In a subcohort of individuals who co-use cocaine and heroin (i.e., speedball), two haplotypes were also significantly associated with HIV infection. One of these involved GPR75, whose ligand, CCL5 (RANTES), is shared with CCR5, a coreceptor for HIV entry. Conclusions Our findings, integrated with long-read human pan-genomes, support a model in which non-functional copies of CYP2D6 disrupt dopaminergic, glutamatergic, and kynurenine pathways in the brain, contributing to cocaine use severity. The association of additional haplotypes with HIV status in speedball users highlights the genetic contribution to comorbid risk in high-exposure populations.