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

Olivia Corradin, Richard Sallari, An T. Hoang, Bibi S Kassim, Gabriella Ben Hutta, Lizette Cuoto, Bryan C. Quach, Katreya Lovrenert, Cameron Hays, Berkley E. Gryder, Marina Iskhakova, Hannah Cates, Yanwei Song, Cynthia F. Bartels, Dana B. Hancock, Deborah C. Mash, Eric O. Johnson, Schahram Akbarian, Peter C. Scacheri
doi: https://doi.org/10.1101/2021.06.15.447736
Olivia Corradin
1Whitehead Institute Biomedical Research
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Richard Sallari
2Axiotl Inc.
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An T. Hoang
1Whitehead Institute Biomedical Research
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Bibi S Kassim
3Department of Psychiatry and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
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Gabriella Ben Hutta
3Department of Psychiatry and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
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Lizette Cuoto
3Department of Psychiatry and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
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Bryan C. Quach
4GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC 27709
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Katreya Lovrenert
5Department of Genetics and Genome Sciences, Case Western Reserve University
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Cameron Hays
6College of Health and Human Services, Western Michigan University
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Berkley E. Gryder
5Department of Genetics and Genome Sciences, Case Western Reserve University
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Marina Iskhakova
3Department of Psychiatry and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
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Hannah Cates
3Department of Psychiatry and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
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Yanwei Song
1Whitehead Institute Biomedical Research
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Cynthia F. Bartels
5Department of Genetics and Genome Sciences, Case Western Reserve University
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Dana B. Hancock
4GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC 27709
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Deborah C. Mash
7Dr. Kiran C. Patel College of Allopathic Medicine, Nova South Eastern University
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Eric O. Johnson
4GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC 27709
8Fellow Program, RTI International, Research Triangle Park, NC 27709, USA
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Schahram Akbarian
3Department of Psychiatry and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
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Peter C. Scacheri
5Department of Genetics and Genome Sciences, Case Western Reserve University
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  • For correspondence: pxs183@case.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 16, 2021.
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Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence
Olivia Corradin, Richard Sallari, An T. Hoang, Bibi S Kassim, Gabriella Ben Hutta, Lizette Cuoto, Bryan C. Quach, Katreya Lovrenert, Cameron Hays, Berkley E. Gryder, Marina Iskhakova, Hannah Cates, Yanwei Song, Cynthia F. Bartels, Dana B. Hancock, Deborah C. Mash, Eric O. Johnson, Schahram Akbarian, Peter C. Scacheri
bioRxiv 2021.06.15.447736; doi: https://doi.org/10.1101/2021.06.15.447736
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Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence
Olivia Corradin, Richard Sallari, An T. Hoang, Bibi S Kassim, Gabriella Ben Hutta, Lizette Cuoto, Bryan C. Quach, Katreya Lovrenert, Cameron Hays, Berkley E. Gryder, Marina Iskhakova, Hannah Cates, Yanwei Song, Cynthia F. Bartels, Dana B. Hancock, Deborah C. Mash, Eric O. Johnson, Schahram Akbarian, Peter C. Scacheri
bioRxiv 2021.06.15.447736; doi: https://doi.org/10.1101/2021.06.15.447736

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