Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence

Corradin, O.; Sallari, R.; Hoang, A. T.; Kassim, B. S.; Ben Hutta, G.; Cuoto, L.; Quach, B. C.; Lovrenert, K.; Hays, C.; Gryder, B. E.; Iskhakova, M.; Cates, H.; Song, Y.; Bartels, C. F.; Hancock, D. B.; Mash, D. C.; Johnson, E. O.; Akbarian, S.; Scacheri, P. C.

doi:10.1101/2021.06.15.447736

bioRxiv · 10.1101/2021.06.15.447736

Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence

Corradin, O.·Sallari, R.·Hoang, A. T.·Kassim, B. S.·Ben Hutta, G.·Cuoto, L.·Quach, B. C.·Lovrenert, K.·Hays, C.·Gryder, B. E.·Iskhakova, M.·Cates, H.·Song, Y.·Bartels, C. F.·Hancock, D. B.·Mash, D. C.·Johnson, E. O.·Akbarian, S.·Scacheri, P. C.

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Abstract

Opioid dependence is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. We interrogated the effects of opioid dependence on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicts case-control status with high accuracy. We focus on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or "plexus": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid dependence and captures genetic and environmental factors perpetuating the opioid epidemic.

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Corradin, O., Sallari, R., Hoang, A. T., Kassim, B. S., Ben Hutta, G., Cuoto, L., Quach, B. C., Lovrenert, K., Hays, C., Gryder, B. E., Iskhakova, M., Cates, H., Song, Y., Bartels, C. F., Hancock, D. B., Mash, D. C., Johnson, E. O., Akbarian, S., Scacheri, P. C.. 2021-06-16. Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence. https://doi.org/10.1101/2021.06.15.447736

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