Abstract

Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this is mostly limited to DNA methylation (5mC). DNA hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD in a male cohort, integrating neuronal-specific 5mC and 5hmC as well as gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD = 26). Single locus methylomic analysis and co-methylation analysis showed a higher number of OUD-associated genes and gene networks for 5hmC compared to 5mC; these were enriched for GPCR, Wnt, neurogenesis, and opioid signaling. 5hmC marks also showed a higher correlation with gene expression patterns and enriched for GWAS of psychiatric traits. Drug interaction analysis revealed interactions with opioid-related drugs, some used as OUD treatments. Our multi-omics findings suggest an important role of 5hmC and reveal loci epigenetically dysregulated in OFC neurons of individuals with OUD.

Opioid use disorder (OUD) is influenced by genetic and environmental factors. Here, authors use a multi-omics approach to reveal DNA hydroxymethylation as an important gene regulatory mechanism for OUD in the human brain.

Details

Title
Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex
Author
Rompala, Gregory 1 ; Nagamatsu, Sheila T. 2   VIAFID ORCID Logo  ; Martínez-Magaña, José Jaime 2   VIAFID ORCID Logo  ; Nuñez-Ríos, Diana L. 2 ; Wang, Jiawei 3   VIAFID ORCID Logo  ; Girgenti, Matthew J. 4   VIAFID ORCID Logo  ; Krystal, John H. 2   VIAFID ORCID Logo  ; Gelernter, Joel 2   VIAFID ORCID Logo  ; Alvarez, Victor E. 5 ; Benedek, David 6 ; Che, Alicia 7 ; Cruz, Dianne A. 8 ; Davis, David A. 9 ; Hoffman, Ellen 7 ; Holtzheimer, Paul E. 10 ; Huber, Bertrand R. 6 ; Kaye, Alfred 7 ; Labadorf, Adam T. 6 ; Keane, Terence M. 11 ; Logue, Mark W. 11 ; McKee, Ann 6 ; Marx, Brian 11 ; Miller, Mark W. 11 ; Noller, Crystal 10 ; Montalvo-Ortiz, Janitza 7 ; Scott, William K. 9 ; Schnurr, Paula 10 ; Stein, Thor 6 ; Ursano, Robert 12 ; Williamson, Douglas E. 8 ; Wolf, Erika J. 11 ; Young, Keith A. 13 ; Hurd, Yasmin L. 1   VIAFID ORCID Logo  ; Montalvo-Ortiz, Janitza L. 2   VIAFID ORCID Logo 

1  Icahn School of Medicine at Mount Sinai, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
2  Yale University School of Medicine, Department of Psychiatry, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); VA Connecticut Healthcare System, West Haven, USA (GRID:grid.281208.1) (ISNI:0000 0004 0419 3073); Clinical Neurosciences Division, U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, USA (GRID:grid.281208.1) 
3  Yale University, Computational Biology and Bioinformatics Program, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Public Health, Department of Biostatistics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
4  Yale University School of Medicine, Department of Psychiatry, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Clinical Neurosciences Division, U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, USA (GRID:grid.47100.32) 
5  Boston University, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
6  Uniformed Services University of the Health Sciences, Bethesda, USA (GRID:grid.265436.0) (ISNI:0000 0001 0421 5525) 
7  Yale University, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
8  Duke University School of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
9  University of Miami, Miami, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606) 
10  National Center for PTSD, Boston, USA (GRID:grid.429666.9) (ISNI:0000 0004 0374 5948); Geisel School of Medicine at Dartmouth, Hanover, USA (GRID:grid.254880.3) (ISNI:0000 0001 2179 2404) 
11  National Center for PTSD, Boston, USA (GRID:grid.429666.9) (ISNI:0000 0004 0374 5948); Uniformed Services University of the Health Sciences, Bethesda, USA (GRID:grid.265436.0) (ISNI:0000 0001 0421 5525) 
12  Geisel School of Medicine at Dartmouth, Hanover, USA (GRID:grid.254880.3) (ISNI:0000 0001 2179 2404) 
13  Texas A&M University, College Station, USA (GRID:grid.264756.4) (ISNI:0000 0004 4687 2082) 
Pages
4544
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-40285-y
ProQuest document ID
2843247887
Copyright
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.