Genetic loci associated with cocaine use identified using a novel approach to detect epistasis
- 1Oregon Research Institute
Abstract
BackgroundCocaine use disorder (CUD) is estimated to be 50% heritable, yet few genetic variants have been robustly associated with risk. During January 2021-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.
ResultsWe 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.
ConclusionsOur 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.
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BibTeX
@misc{garvin2026genetic,
title = {{Genetic loci associated with cocaine use identified using a novel approach to detect epistasis}},
author = {M. R. Garvin and A. W. Bergen and D. M. Rosenblum and D. Kainer and S. Climer and J. J. Goedert and P. J. Attia and S. Peng and Q. Zhang and S. H. Weiss},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.26365448},
url = {https://www.medrxiv.org/content/10.64898/2026.10.13.26365448v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Genetic loci associated with cocaine use identified using a novel approach to detect epistasis
AU - M. R. Garvin
AU - A. W. Bergen
AU - D. M. Rosenblum
AU - D. Kainer
AU - S. Climer
AU - J. J. Goedert
AU - P. J. Attia
AU - S. Peng
AU - Q. Zhang
AU - S. H. Weiss
PY - 2026
DA - 2026/10/13
PB - medRxiv
DO - 10.64898/2026.10.13.26365448
UR - https://www.medrxiv.org/content/10.64898/2026.10.13.26365448v1
AB - BackgroundCocaine use disorder (CUD) is estimated to be 50% heritable, yet few genetic variants have been robustly associated with risk. During January 2021-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. ResultsWe 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. ConclusionsOur 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.
ER -