Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

Gregory Rompala, Sheila T. Nagamatsu, José Jaime Martínez-Magaña, Diana L. Nuñez-Ríos, Jiawei Wang, Matthew J. Girgenti, John H. Krystal, Joel Gelernter, Yasmin L. Hurd and Janitza L. Montalvo-Ortiz ()
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Gregory Rompala: Icahn School of Medicine at Mount Sinai
Sheila T. Nagamatsu: Yale University School of Medicine
José Jaime Martínez-Magaña: Yale University School of Medicine
Diana L. Nuñez-Ríos: Yale University School of Medicine
Jiawei Wang: Yale University
Matthew J. Girgenti: Yale University School of Medicine
John H. Krystal: Yale University School of Medicine
Joel Gelernter: Yale University School of Medicine
Yasmin L. Hurd: Icahn School of Medicine at Mount Sinai
Janitza L. Montalvo-Ortiz: Yale University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40285-y

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