Glypican Gene GPC5 Participates in the Behavioral Response to Ethanol: Evidence from Humans, Mice, and Fruit Flies.
Glypican Gene GPC5 Participates in the Behavioral Response to Ethanol: Evidence from Humans, Mice, and Fruit Flies.
复制标题
DOI：
10.1534/g3.111.000976
复制
发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
White RL
中科院分区：
文献类型：
--
作者：
Joslyn G;Wolf FW;Brush G;Wu L;Schuckit M;White RL
酒精使用障碍受到许多相互作用的遗传和环境因素的影响。突出这种复杂性的是观察到的大基因组范围的关联实验涉及许多基因的弱统计支持。实验模型系统，细胞培养和动物，已经确定了许多基因和途径参与乙醇的反应，但其适用于酒精使用障碍的发展在人类是不确定的。为了克服任何单一实验系统的局限性，这里使用的分析策略是识别在多个实验系统中发挥共同表型效应的基因。具体来说，我们（1）进行了小鼠连锁分析，以确定影响乙醇诱导的共济失调的数量性状基因座;（2）对小鼠确定的基因座进行了人类遗传关联分析，以对抗乙醇诱导的身体摇摆，这种表型不仅与小鼠乙醇-共济失调表型相当，而且是酒精使用障碍的遗传影响的内在表型;（3）在果蝇中进行的行为遗传学实验表明，人类和小鼠遗传分析所涉及的磷脂酰肌醇蛋白聚糖基因家族的成员GPC 5的果蝇同源物影响果蝇对乙醇的反应;和（4）从文献中发现的数据表明，遗传上涉及的基因的表达不仅在时间和空间上与乙醇的参与一致，诱导的行为，但也调制乙醇。这些数据的融合为GPC 5参与细胞和生物体乙醇反应以及人类酒精使用障碍的病因学的假设提供了强有力的支持。
Alcohol use disorders are influenced by many interacting genetic and environmental factors. Highlighting this complexity is the observation that large genome-wide association experiments have implicated many genes with weak statistical support. Experimental model systems, cell culture and animal, have identified many genes and pathways involved in ethanol response, but their applicability to the development of alcohol use disorders in humans is undetermined. To overcome the limitations of any single experimental system, the analytical strategy used here was to identify genes that exert common phenotypic effects across multiple experimental systems. Specifically, we (1) performed a mouse linkage analysis to identify quantitative trait loci that influence ethanol-induced ataxia; (2) performed a human genetic association analysis of the mouse-identified loci against ethanol-induced body sway, a phenotype that is not only comparable to the mouse ethanol-ataxia phenotype but is also a genetically influenced endophenotype of alcohol use disorders; (3) performed behavioral genetic experiments in Drosophila showing that fly homologs of GPC5, the member of the glypican gene family implicated by both the human and mouse genetic analyses, influence the fly’s response to ethanol; and (4) discovered data from the literature demonstrating that the genetically implicated gene’s expression is not only temporally and spatially consistent with involvement in ethanol-induced behaviors but is also modulated by ethanol. The convergence of these data provides strong support to the hypothesis that GPC5 is involved in cellular and organismal ethanol response and the etiology of alcohol use disorders in humans.
登录
查看更多内容
DOI：
10.1111/j.1530-0277.2009.01093.x
发表时间：
2010-02
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Kong EC;Allouche L;Chapot PA;Vranizan K;Moore MS;Heberlein U;Wolf FW
通讯作者：
Wolf FW
影响因子：
5.7
作者：
Budnik V;Salinas PC
通讯作者：
Salinas PC
影响因子：
12.3
作者：
Filmus J;Capurro M;Rast J
通讯作者：
Rast J
DOI：
10.1111/j.1530-0277.2010.01156.x
发表时间：
2010-05
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Edenberg HJ;Koller DL;Xuei X;Wetherill L;McClintick JN;Almasy L;Bierut LJ;Bucholz KK;Goate A;Aliev F;Dick D;Hesselbrock V;Hinrichs A;Kramer J;Kuperman S;Nurnberger JI Jr;Rice JP;Schuckit MA;Taylor R;Todd Webb B;Tischfield JA;Porjesz B;Foroud T
通讯作者：
Foroud T
DOI：
10.1111/j.1530-0277.2010.01152.x
发表时间：
2010-05-01
影响因子：
3.2
作者：
Joslyn, Geoff;Ravindranathan, Ajay;White, Raymond L.
通讯作者：
White, Raymond L.