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Chunk #44 — Discussion

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RNA alternative splicing impacts the risk for alcohol use disorder.
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The adapted MR approach enabled us to identify six exon skipping events that impact AUD susceptibility. Interestingly, four of the five exons in protein coding genes are in the untranslated regions and two of these changed the expression of their host genes (ELOVL7 and NSUN4), suggesting that they may be involved in post-transcriptional regulation. Of note, ELOVL7, was previously identified as down-regulated in prefrontal cortex in individuals with alcohol dependence [52]. DRC1 encodes a critical component involved in regulating ciliary dynein motors that are targeted by alcohol-induced ciliary dysfunction [54]. NSUN4 and SRRM2 are both involved in neurological disorders [50, 51]; in particular, SRRM2, a splicing factor, regulates ethanol-cue-induced memory in flies [67]. Alcohol downregulates TBC1D5, which contributes to alcoholic liver disease as well as to Parkinson’s disease and Alzheimer’s disease [68]. Additionally, LINC00665 is an emerging cancer biomarker, including in glioma and alcohol-related cancers (e.g., breast cancer and liver cancer) [69–71].