Mulligan Megan K, Ponomarev Igor, Hitzemann Robert J, Belknap John K, Tabakoff Boris, Harris R Adron, Crabbe John C, Blednov Yuri A, Grahame Nicholas J, Phillips Tamara J, Finn Deborah A, Hoffman Paula L, Iyer Vishwanath R, Koob George F, Bergeson Susan E
Waggoner Center for Alcohol and Addiction Research and Sections of Neurobiology, University of Texas, Austin, TX 78712, USA.
Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6368-73. doi: 10.1073/pnas.0510188103. Epub 2006 Apr 17.
Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.
来自人类和动物研究的大量证据支持这样一种假说，即酒精成瘾是一种受遗传和环境因素影响的复杂疾病。在人类中研究过量饮酒的分子决定因素很困难。然而，几种啮齿动物模型显示出对酒精的高偏好或低偏好，这为研究饮酒遗传易感性背后的分子复杂性提供了独特的机会。对三个选定品系以及六个已知在自愿饮酒量上有显著差异的同基因小鼠品系的大脑基因表达进行微阵列分析，为荟萃分析提供了超过450万个数据点。总共获得了107个微阵列，并将其安排成六个实验数据集，从而能够识别出在所有高饮酒量或低饮酒量模型之间显著且一致变化的3800个独特基因。发现包括丝裂原活化蛋白激酶信号传导和转录调控途径在内的几个功能组显著富集，并且可能在这些小鼠模型中建立高水平的自愿饮酒行为中起重要作用。来自一般荟萃分析的数据通过一个同源近交系微阵列集进一步筛选，从中鉴定出位于9号染色体上的酒精偏好数量性状位点的顺式调控候选基因：Arhgef12、Carm1、Cryab、Cox5a、Dlat、Fxyd6、Limd1、Nicn1、Nmnat3、Pknox2、Rbp1、Sc5d、Scn4b、Tcf12、Vps11、Zfp291和四个EST。本研究展示了（i）使用微阵列荟萃分析来分析一种行为表型（在本案例中为酒精偏好）以及（ii）使用同源近交系来鉴定顺式调控。
