RNA alternative splicing impacts the risk for alcohol use disorder

Abstract

Alcohol use disorder (AUD) is a complex genetic disorder characterized by problems arising from excessive alcohol consumption. Identifying functional genetic variations that contribute to risk for AUD is a major goal. Alternative splicing of RNA mediates the flow of genetic information from DNA to gene expression and expands proteome diversity. We asked whether alternative splicing could be a risk factor for AUD. Herein, we used a Mendelian randomization (MR)-based approach to identify skipped exons (the predominant splicing event in brain) that contribute to AUD risk. Genotypes and RNA-seq data from the CommonMind Consortium were used as the training dataset to develop predictive models linking individual genotypes to exon skipping in the prefrontal cortex. We applied these models to data from the Collaborative Studies on Genetics of Alcoholism to examine the association between the imputed cis-regulated splicing outcome and the AUD-related traits. We identified 27 exon skipping events that were predicted to affect AUD risk; six of these were replicated in the Australian Twin-family Study of Alcohol Use Disorder. Their host genes are DRC1, ELOVL7, LINC00665, NSUN4, SRRM2 and TBC1D5. The genes downstream of these splicing events are enriched in neuroimmune pathways. The MR-inferred impacts of the ELOVL7 skipped exon on AUD risk was further supported in four additional large-scale genome-wide association studies. Additionally, this exon contributed to changes of gray matter volumes in multiple brain regions, including the visual cortex known to be involved in AUD. In conclusion, this study provides strong evidence that RNA alternative splicing impacts the susceptibility to AUD and adds new information on AUD-relevant genes and pathways. Our framework is also applicable to other types of splicing events and to other complex genetic disorders.

It is not just about transcription: involvement of brain RNA splicing in substance use disorders

“…However, when alternative splicing becomes dysregulated, it may lead to the production of dysfunctional proteins or disrupt vital cellular processes, contributing to the onset and progression of neurological and psychiatric diseases (Nik and Bowman 2019 ). Studies indicate that exposure to drugs of abuse results in alternatively spliced transcripts in different brain regions, potentially contributing to the development of SUDs (Van Booven et al 2021 ; Xu et al 2014 , 2021 ; Piltonen et al 2021 ; Huggett et al 2022 ; Li et al 2023 ; Krapacher et al 2022 ).…”

“…Finally, recent studies have highlighted that alternative splicing may contribute to the risk of AUD, in addition to being altered by alcohol exposure (Li et al 2023 ; Lusk et al 2022 ; Huggett et al 2022 ). In a recent study, Huggett et al ( 2023 ) utilized RNA-Seq data from three brain regions (prefrontal cortex, nucleus accumbens, and amygdala) in individuals diagnosed with AUD ( n = 56; ages 40–73; 100% ‘Caucasian’).…”

“…In a separate study, a Mendelian randomization-based approach applied to the Collaborative Studies on the Genetics of Alcoholism (COGA) data identified 27 exon-skipping events predicted to influence AUD risk. For instance, the skipping of the second exon within the ELOVL fatty acid elongase 7 ( ELOVL7 ) gene showed strong associations with alcohol dependence and problematic drinking (Li et al 2023 ). This exon was also found to contribute to alterations in gray matter volumes across various brain regions, including the visual cortex, a region implicated in AUD (Li et al 2023 ).…”

“…For instance, the skipping of the second exon within the ELOVL fatty acid elongase 7 ( ELOVL7 ) gene showed strong associations with alcohol dependence and problematic drinking (Li et al 2023 ). This exon was also found to contribute to alterations in gray matter volumes across various brain regions, including the visual cortex, a region implicated in AUD (Li et al 2023 ). In rats, a predisposition to voluntary alcohol consumption trait in the two-bottle choice paradigm was associated with specific isoforms from genes related to brain inflammation and the immune response (e.g., Lrap , Ift81 , and P2rx4 ) (Lusk et al 2022 ).…”