Muir William M, Lo Chiao-Ling, Bell Richard L, Zhou Feng C
Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
Alcohol Clin Exp Res (Hoboken). 2023 Aug;47(8):1478-1493. doi: 10.1111/acer.15131. Epub 2023 Jul 2.
The basis for familial alcohol use disorder (AUD) remains an enigma due to various biological and societal confounds. The present study used three of the most adopted and documented rat models, combining the alcohol-preferring/non-alcohol-preferring (P/NP) lines and high alcohol-drinking/low alcohol-drinking (HAD/LAD) replicated lines, of AUD as examined through the lens of whole genomic analyses.
We used complete genome sequencing of the P/NP lines and previously published sequences of the HAD/LAD replicates to enhance the discovery of variants associated with AUD 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 the direction of selection, that is, ethanol-drinking preference.
Our first finding was that in addition to variants causing translational changes, the principal genetic changes associated with drinking predisposition were silent mutations and mutations in the 3' untranslated regions (3'UTR) of genes. Neither of these types of mutations alters the amino acid sequence of the translated protein but they influence both the rate and conformation of gene transcription, including its stability and posttranslational events that alter gene efficacy. This finding argues for refocusing human genomic studies on changes in gene efficacy. Among the key ontologies identified were the central genes associated with the Na+ voltage-gated channels of neurons and glia (including the Scn1a, Scn2a, Scn2b, Scn3a, Scn7a, and Scn9a subtypes) and excitatory glutamatergic secretion (including Grm2 and Myo6), both of which are essential in neuroplasticity. In addition, we identified "Nociception or Sensory Perception of Pain," which contained variants in nociception (Arrb1, Ccl3, Ephb1) and enlist sodium (Scn1a, Scn2a, Scn2b, Scn3a, Scn7a), pain activation (Scn9a), and potassium channel (Kcna1) genes.
The multi-model analyses used herein reduced the confounding effects of random drift and the "founders" genetic background. The most differentiated bidirectionally selected genes across all three animal models were Scn9a, Scn1a, and Kcna, all of which are annotated in the nociception ontology. The complexity of neuroplasticity and nociception adds strength to the hypothesis that neuroplasticity and pain (physical or psychological) are prominent phenotypes genetically linked to the development of AUD.
由于各种生物学和社会混杂因素，家族性酒精使用障碍（AUD）的病因仍是一个谜。本研究使用了三种最常用且有文献记载的大鼠模型，结合了酒精偏好/非酒精偏好（P/NP）品系和高饮酒量/低饮酒量（HAD/LAD）重复品系，通过全基因组分析来研究AUD。
我们对P/NP品系进行了全基因组测序，并使用了先前发表的HAD/LAD重复品系的序列，以增强与AUD相关变异的发现，并消除遗传背景和随机遗传漂变的混杂影响。具体而言，我们使用高阶统计方法来搜索基因变异，这些变异在整个基因本体集中的频率变化与选择方向上的表型变化相对应，即乙醇饮用偏好。
我们的第一个发现是，除了导致翻译变化的变异外，与饮酒易感性相关的主要遗传变化是沉默突变和基因3'非翻译区（3'UTR）的突变。这两种类型的突变都不会改变翻译后蛋白质的氨基酸序列，但它们会影响基因转录的速率和构象，包括其稳定性和改变基因效力的翻译后事件。这一发现支持将人类基因组研究重新聚焦于基因效力的变化。在确定的关键本体中，有与神经元和神经胶质细胞的Na+电压门控通道相关的核心基因（包括Scn1a、Scn2a、Scn2b、Scn3a、Scn7a和Scn9a亚型）以及兴奋性谷氨酸能分泌相关基因（包括Grm2和Myo6），这两者在神经可塑性中都至关重要。此外，我们还确定了“伤害感受或疼痛的感觉知觉”，其中包含伤害感受（Arrb1、Ccl3、Ephb1）和钠募集（Scn1a、Scn2a、Scn2b、Scn3a、Scn7a）、疼痛激活（Scn9a）以及钾通道（Kcna1）基因中的变异。
本文使用的多模型分析减少了随机漂变和“奠基者”遗传背景的混杂效应。在所有三种动物模型中差异最大的双向选择基因是Scn9a、Scn1a和Kcna，所有这些基因都在伤害感受本体中注释。神经可塑性和伤害感受的复杂性进一步支持了以下假设：神经可塑性和疼痛（身体或心理）是与AUD发展在遗传上相关的突出表型。
