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Chunk #45 — Discussion

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RNA alternative splicing impacts the risk for alcohol use disorder.
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Additionally, of the 970 genes that are potentially regulated by at least one of the five analyzable skipped exons, 197 (20%, Supplementary Table S4) were responsive to alcohol in a cell culture study [57]. Among these genes, 20 have also been identified as alcohol-responsive in human and animal studies, further increasing their relevance to AUD. Together, these findings indicate that expression changes of these 197 genes are not simply an effect of alcohol intake, but rather, the expression of these genes contribute to the genetic basis of AUD. Two additional genes, OAS3 (2’-5’-Oligoadenylate Synthetase 3) and OXTR (Oxytocin Receptor) show evidence in the NHGRI GWAS catalog for association with alcohol consumption and dependence, respectively. OAS3 is an interferon (IFN-α/β or γ)-induced, dsRNA-activated oligoadenylate synthase that plays a critical role in cellular antiviral response. OXTR is a G-protein coupled receptor for oxytocin, which is known to play a role in neuropsychiatric disorders, including alcohol and drug addiction [72, 73]. Moreover, we found that Hsp70/HSPA6 was differentially expressed as a result of genetic variant-induced splicing changes in any of the three skipped