Department of Psychology, Binghamton University, Binghamton, NY, USA.
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
Alcohol Clin Exp Res. 2021 Apr;45(4):697-708. doi: 10.1111/acer.14582. Epub 2021 Apr 7.
Interindividual variation in voluntary ethanol consumption and ethanol response is partially influenced by genetic variation. Discovery of the genes and allelic variants that affect these phenotypes may clarify the etiology and pathophysiology of problematic alcohol use, including alcohol use disorder. Genetically diverse mouse populations, which demonstrate heritable variation in ethanol consumption, can be utilized to discover the genes and gene networks that influence this trait. The Collaborative Cross (CC) recombinant inbred strains, Diversity Outbred (DO) population and their 8 founder strains are complementary mouse resources that capture substantial genetic diversity and can demonstrate expansive phenotypic variation in heritable traits. These populations may be utilized to discover candidate genes and gene networks that moderate ethanol consumption and other ethanol-related traits.
We characterized ethanol consumption, preference, and pharmacokinetics in the 8 founder strains and 10 CC strains in 12-hour drinking sessions during the dark phase of the circadian cycle.
Ethanol consumption was substantially heritable, both early in ethanol access and over a chronic intermittent access schedule. Ethanol pharmacokinetics were also heritable; however, no association between strain-level ethanol consumption and pharmacokinetics was detected. The PWK/PhJ strain was the highest drinking strain, with consumption substantially exceeding that of the C57BL/6J strain, which is commonly used as a model of "high" or "binge" drinking. Notably, we found strong evidence that sex moderated genetic effects on voluntary ethanol drinking.
Collectively, this research serves as a foundation for expanded genetic study of ethanol consumption in the CC/DO and related populations. Moreover, we identified reference strains with extreme consumption phenotypes that effectively represent polygenic models of excessive ethanol use.
个体间自愿饮酒和对乙醇的反应差异部分受遗传变异的影响。发现影响这些表型的基因和等位基因变异，可能会阐明包括酒精使用障碍在内的问题性饮酒的病因和病理生理学。具有可遗传的乙醇消耗变异的遗传多样性小鼠群体可用于发现影响该特征的基因和基因网络。合作交叉（CC）重组近交系、多样性远交（DO）群体及其 8 个创始系是互补的小鼠资源，它们捕获了大量的遗传多样性，并能在可遗传特征方面展示出广泛的表型变异。这些群体可用于发现调节乙醇消耗和其他乙醇相关特征的候选基因和基因网络。
我们在昼夜节律周期的暗期 12 小时的饮酒期间，对 8 个创始系和 10 个 CC 系进行了乙醇消耗、偏好和药代动力学的特征描述。
乙醇消耗具有很强的遗传性，无论是在早期乙醇摄入还是慢性间歇性摄入期间。乙醇药代动力学也具有遗传性；然而，没有检测到菌株水平的乙醇消耗与药代动力学之间的关联。PWK/PhJ 株是最高饮酒株，其消耗量大大超过了通常用作“高”或“狂欢”饮酒模型的 C57BL/6J 株。值得注意的是，我们发现强有力的证据表明，性别调节了遗传效应对自愿性乙醇摄入的影响。
总的来说，这项研究为 CC/DO 及相关群体中乙醇消耗的扩展遗传研究奠定了基础。此外，我们确定了具有极端消耗表型的参考株，它们有效地代表了多基因模型的过度乙醇使用。
