Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose
Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interroga...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2022
|
| Online Access: | https://hdl.handle.net/1721.1/146782 |
| _version_ | 1826207829434826752 |
|---|---|
| author | Corradin, Olivia Sallari, Richard Hoang, An T Kassim, Bibi S Ben Hutta, Gabriella Cuoto, Lizette Quach, Bryan C Lovrenert, Katreya Hays, Cameron Gryder, Berkley E Iskhakova, Marina Cates, Hannah Song, Yanwei Bartels, Cynthia F Hancock, Dana B Mash, Deborah C Johnson, Eric O Akbarian, Schahram Scacheri, Peter C |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Corradin, Olivia Sallari, Richard Hoang, An T Kassim, Bibi S Ben Hutta, Gabriella Cuoto, Lizette Quach, Bryan C Lovrenert, Katreya Hays, Cameron Gryder, Berkley E Iskhakova, Marina Cates, Hannah Song, Yanwei Bartels, Cynthia F Hancock, Dana B Mash, Deborah C Johnson, Eric O Akbarian, Schahram Scacheri, Peter C |
| author_sort | Corradin, Olivia |
| collection | MIT |
| description | Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose 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 predicted case-control status with high accuracy. We focused 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 use disorder and captures genetic and environmental factors perpetuating the opioid epidemic. |
| first_indexed | 2024-09-23T13:55:36Z |
| format | Article |
| id | mit-1721.1/146782 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:55:36Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1467822022-12-08T03:19:09Z Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose Corradin, Olivia Sallari, Richard Hoang, An T Kassim, Bibi S Ben Hutta, Gabriella Cuoto, Lizette Quach, Bryan C Lovrenert, Katreya Hays, Cameron Gryder, Berkley E Iskhakova, Marina Cates, Hannah Song, Yanwei Bartels, Cynthia F Hancock, Dana B Mash, Deborah C Johnson, Eric O Akbarian, Schahram Scacheri, Peter C Massachusetts Institute of Technology. Department of Biology Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose 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 predicted case-control status with high accuracy. We focused 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 use disorder and captures genetic and environmental factors perpetuating the opioid epidemic. 2022-12-07T16:48:21Z 2022-12-07T16:48:21Z 2022 2022-12-07T16:42:43Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146782 Corradin, Olivia, Sallari, Richard, Hoang, An T, Kassim, Bibi S, Ben Hutta, Gabriella et al. 2022. "Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose." Molecular Psychiatry, 27 (4). en 10.1038/S41380-022-01477-Y Molecular Psychiatry Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Corradin, Olivia Sallari, Richard Hoang, An T Kassim, Bibi S Ben Hutta, Gabriella Cuoto, Lizette Quach, Bryan C Lovrenert, Katreya Hays, Cameron Gryder, Berkley E Iskhakova, Marina Cates, Hannah Song, Yanwei Bartels, Cynthia F Hancock, Dana B Mash, Deborah C Johnson, Eric O Akbarian, Schahram Scacheri, Peter C Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| title | Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| title_full | Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| title_fullStr | Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| title_full_unstemmed | Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| title_short | Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| title_sort | convergence of case specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose |
| url | https://hdl.handle.net/1721.1/146782 |
| work_keys_str_mv | AT corradinolivia convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT sallaririchard convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT hoangant convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT kassimbibis convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT benhuttagabriella convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT cuotolizette convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT quachbryanc convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT lovrenertkatreya convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT hayscameron convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT gryderberkleye convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT iskhakovamarina convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT cateshannah convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT songyanwei convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT bartelscynthiaf convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT hancockdanab convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT mashdeborahc convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT johnsonerico convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT akbarianschahram convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose AT scacheripeterc convergenceofcasespecificepigeneticalterationsidentifyaconfluenceofgeneticvulnerabilitiestiedtoopioidoverdose |