Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.
As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P < 0.025) with several LR phenotypes in a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs.alcohol use disorders ͉ genetics ͉ quantitative trait locus M ultiple genetic and environmental components contribute to alcohol use disorders (AUDs) (1). As with other genetically complex common psychiatric and medical conditions, it is challenging to match genetic variants with the disease phenotype. Intermediate phenotypes, such as the large numbers of colon polyps seen in the familial polyposis form of colon cancer (2), are often closer to the underlying biology and may provide a better phenotype for genetic analysis (3).The level of response (LR) to alcohol has been developed as an intermediate phenotype for AUDs (4). Physical responses (e.g., body sway) and subjective feelings (as measured on the Subjective High Assessment Scale [SHAS]) show reproducible individual variation among subjects. Prospective studies have shown that individuals with a low LR are at increased risk for AUDs (5). Alcohol LR is heritable, on a par with alcohol dependence, with genes explaining 40% to 60% of the variance (6-8). Linkage analyses have shown interesting but inconclusive findings (9-11).Frequent concurrence of alcohol and nicotine use and dependence suggests a shared etiology (12). Twin studies (13-16) conclude there are shared genetic factors that influence alcohol and nicotine consumption and dependence. Functional evidence that nicotinic receptors are involved in alcohol responses is provided by studies showing that mice treated with the smoking cessation drug varenicline, a nicotinic receptor partial agonist, have an attenuated response to alcohol; they drink less and show reduced levels of reinstatement following alcohol abstinence (17)....
Background: Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs.Methods: A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected.Results: The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population.Conclusions: These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects.
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