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Multi-animal model study reveals mutations in neural plasticity and nociception genes are linked to excessive alcohol drinking.

W. Muir,Chiao-Ling Lo,R. Bell,F. Zhou

Published 2023 in Alcohol

ABSTRACT

BACKGROUND Familial alcohol use disorder (AUD) remains an enigma due to various biological and societal confounds. The present study used two of the most adopted and documented rat models, combining the P/NP lines and HAD/LAD replicated lines, of alcoholism as examined through the lens of whole genomic analyses. METHODS We used complete genome sequencing of the P/NP lines and previous published sequences of the HAD/LAD replicates to enhance discovery of variants associated with AUDs and to remove confounding with genetic background and random genetic drift. Specifically, we used high-order statistical methods to search for genetic variants whose frequency changes in whole sets of gene ontologies corresponded with phenotypic changes in direction of selection, i.e., ethanol drinking preference. RESULTS Our first crucial finding was that in addition to variants causing translational changes, the principal genetic changes associated with drinking pre-disposition were so called "Silent Mutations" and mutations in the 3' untranslated regions (3'UTR). Neither of these alter the amino acid sequence translated, but instead influence both the rate and conformation of gene transcription, including stability and post-translation events that change gene efficacy. This finding advocates for a refocusing on changes in gene-efficacy in human genomic studies. Among the key ontologies identified was the "Nociception or Sensory Perception of Pain", which contained variants not only in nociception (Arrb1, Ccl3, Ephb1) but also enlists sodium (Scn1a, Scn2a, Scn2b, Scn3a, Scn7a), pain activation (Scn9a), and potassium channel (Kcna1) genes. CONCLUSION The multi-model analys s used herein largely resolved the confounding effects of random drift and the "founders" genetic background. This allowed for a deeper scrutiny of key genetic features associated with familial AUD. The most differentiated bidirectionally selected genes across all 3 animal models were Scn9a, Scn1a and Kcna1, all of which are annotated in the Nociception or Sensory Perception of Pain ontology. The complexity of nociception adds strength to the hypothesis that "pain" (physical or psychological) is a prominent phenotype genetically linked to the development of AUDs. This article is protected by copyright. All rights reserved.

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