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Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry
Opiate/opioid use disorder (OUD) is a chronic relapsing brain disorder that has increased in prevalence in the last two decades in the United States. Understanding the molecular correlates of OUD may provide key insights into the pathophysiology of this syndrome. Using publicly available RNA-sequenc...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9222793/ https://www.ncbi.nlm.nih.gov/pubmed/35741807 http://dx.doi.org/10.3390/genes13061045 |
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author | Huggett, Spencer B. Ikeda, Ami S. McGeary, John E. Kaun, Karla R. Palmer, Rohan H. C. |
author_facet | Huggett, Spencer B. Ikeda, Ami S. McGeary, John E. Kaun, Karla R. Palmer, Rohan H. C. |
author_sort | Huggett, Spencer B. |
collection | PubMed |
description | Opiate/opioid use disorder (OUD) is a chronic relapsing brain disorder that has increased in prevalence in the last two decades in the United States. Understanding the molecular correlates of OUD may provide key insights into the pathophysiology of this syndrome. Using publicly available RNA-sequencing data, our study investigated the possible role of alternative mRNA splicing in human brain tissue (dorsal–lateral prefrontal cortex (dlPFC), nucleus accumbens (NAc), and midbrain) of 90 individuals with OUD or matched controls. We found a total of 788 differentially spliced genes across brain regions. Alternative mRNA splicing demonstrated mostly tissue-specific effects, but a functionally characterized splicing change in the clathrin and AP-2-binding (CLAP) domain of the Bridging Integrator 1 (BIN1) gene was significantly linked to OUD across all brain regions. We investigated two hypotheses that may underlie differential splicing in OUD. First, we tested whether spliceosome genes were disrupted in the brains of individuals with OUD. Pathway enrichment analyses indicated spliceosome perturbations in OUD across brain regions. Second, we tested whether alternative mRNA splicing regions were linked to genetic predisposition. Using a genome-wide association study (GWAS) of OUD, we found no evidence that DNA variants within or surrounding differentially spliced genes were implicated in the heritability of OUD. Altogether, our study contributes to the understanding of OUD pathophysiology by providing evidence of a possible role of alternative mRNA splicing in OUD. |
format | Online Article Text |
id | pubmed-9222793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92227932022-06-24 Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry Huggett, Spencer B. Ikeda, Ami S. McGeary, John E. Kaun, Karla R. Palmer, Rohan H. C. Genes (Basel) Article Opiate/opioid use disorder (OUD) is a chronic relapsing brain disorder that has increased in prevalence in the last two decades in the United States. Understanding the molecular correlates of OUD may provide key insights into the pathophysiology of this syndrome. Using publicly available RNA-sequencing data, our study investigated the possible role of alternative mRNA splicing in human brain tissue (dorsal–lateral prefrontal cortex (dlPFC), nucleus accumbens (NAc), and midbrain) of 90 individuals with OUD or matched controls. We found a total of 788 differentially spliced genes across brain regions. Alternative mRNA splicing demonstrated mostly tissue-specific effects, but a functionally characterized splicing change in the clathrin and AP-2-binding (CLAP) domain of the Bridging Integrator 1 (BIN1) gene was significantly linked to OUD across all brain regions. We investigated two hypotheses that may underlie differential splicing in OUD. First, we tested whether spliceosome genes were disrupted in the brains of individuals with OUD. Pathway enrichment analyses indicated spliceosome perturbations in OUD across brain regions. Second, we tested whether alternative mRNA splicing regions were linked to genetic predisposition. Using a genome-wide association study (GWAS) of OUD, we found no evidence that DNA variants within or surrounding differentially spliced genes were implicated in the heritability of OUD. Altogether, our study contributes to the understanding of OUD pathophysiology by providing evidence of a possible role of alternative mRNA splicing in OUD. MDPI 2022-06-10 /pmc/articles/PMC9222793/ /pubmed/35741807 http://dx.doi.org/10.3390/genes13061045 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Huggett, Spencer B. Ikeda, Ami S. McGeary, John E. Kaun, Karla R. Palmer, Rohan H. C. Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry |
title | Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry |
title_full | Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry |
title_fullStr | Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry |
title_full_unstemmed | Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry |
title_short | Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry |
title_sort | opioid use disorder and alternative mrna splicing in reward circuitry |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9222793/ https://www.ncbi.nlm.nih.gov/pubmed/35741807 http://dx.doi.org/10.3390/genes13061045 |
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