The Search for Genes Contributing to the Low Level of Response to Alcohol: Patterns of Findings Across Studies

Schuckit, Marc A.; Smith, Tom L.; Kalmijn, Jelger

doi:10.1097/01.alc.0000141637.01925.f6

Cited by 145 publications

(98 citation statements)

References 152 publications

(157 reference statements)

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“…Although the percent homology shared by mammalian AUTS2 and Drosophila tay proteins is low, a neurological role for Drosophila tay has been described (24). A low level of response to alcohol has been identified as a risk factor for alcohol dependence in both human and animal studies (25,26). Thus, our functional genetic experiments provide evidence for the involvement of AUTS2 in alcohol drinking behavior across three different species.…”

Section: Discussionmentioning

confidence: 69%

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Schumann

Coin

Lourdusamy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

258

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Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples ( P = 0.026) and significant ( P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

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Section: Discussionmentioning

confidence: 69%

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Schumann

Coin

Lourdusamy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

258

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“…This finding may be specific to the rotarod, as strain correlational studies have shown that different assays of ethanol intoxication tend to be influenced by different genes . It is of interest, however, as a substantial human literature has found a genetic relationship between low sensitivity to alcohol and eventual diagnosis of alcohol dependence in offspring with a positive family history (Schuckit, 1994;Schuckit et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Voluntary ethanol consumption in 22 inbred mouse strains

Yoneyama

Crabbe

Ford

et al. 2008

Alcohol

272

269

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Inbred strains are genetically stable across time and laboratories, allowing scientists to accumulate a record of phenotypes, including physiological characteristics and behaviors. To date, the C57/C58 family of inbred mouse strains has been identified as having the highest innate ethanol consumption, but some lineages have rarely or never been surveyed. Thus, the purpose of the present experiment was to measure ethanol preference and intake in 22 inbred mouse strains, some of which have never been tested for ethanol consumption. Male and female mice (A/J, BALB/cByJ, BTBR+T tf/tf , BUB/ BnJ, C57BL/6J, C57BLKS/J, C58/J, CZECH/Ei, DBA/2J, FVB/NJ, I/LnJ, LP/J, MA/MyJ, NOD/ LtJ, NON/LtJ, NZB/B1NJ, NZW/LacJ, PERA/Ei, RIIIS/J, SEA/GnJ, SM/J, and 129S1/SvlmJ) were individually housed and given unlimited access in a two-bottle choice procedure to one bottle containing tap water and a second containing increasing concentrations of ethanol (3%, 6%, 10%), 0.2% saccharin, and then increasing concentrations of ethanol (3%, 6%, 10%) plus 0.2% saccharin. Mice were given access to each novel solution for a total of 4 days, with a bottle side change every other day. Consistent with previous studies, C57BL/6J (B6) mice consumed an ethanol dose of > 10g/kg/day while DBA/2J (D2) mice consumed < 2g/kg/day. No strain voluntarily consumed greater doses of ethanol than B6 mice. While the C58 and C57BLKS strains showed high ethanol consumption levels that were comparable to B6 mice, the BUB and BTBR strains exhibited low ethanol intakes similar to D2 mice. The addition of 0.2% saccharin to the ethanol solutions significantly increased ethanol intake by most strains and altered the strain distribution pattern. Strong positive correlations (rs ≥ 0.83) were determined between consumption of the unsweetened versus sweetened ethanol solutions. Consumption of saccharin alone was significantly positively correlated with the sweetened ethanol solutions (rs = 0.62 -0.81), but the correlation with unsweetened ethanol solutions was considerably lower (rs = 0.37 -0.45). These results add new strains to the strain mean database that will facilitate the identification of genetic relationships between voluntary ethanol consumption, saccharin preference, and other phenotypes.

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“…One behavioral characteristic related to this risk is a low level of response to an acute alcohol challenge (Schuckit, 1998), a trait that carries a similar estimated heritability of 40-60% (Schuckit and Smith, 1996;Heath et al, 1999). Linkage studies have identified regions on chromosomes 10, 11, 13, and 20 with LOD scores X3.0 that may contain genes that contribute to the level of response to alcohol (Schuckit et al, 2004). Few genes have been identified, although recently the long allele of the SLC6A4 gene, which encodes the serotonin transporter, and the Ser 385 variant of the GABRA6 gene, which encodes the a6 subunit of GABA A receptors, have been associated with a low level of response to alcohol in humans (Hu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The Collaborative Study on the Genetics of Alcoholism has identified the GABRA2 gene located on chromosome 4 encoding the a2-subunit of the GABA A receptor, the GABRB1 gene on chromosome 4 coding for the b1 subunit of the GABA A receptor, and the CHRM2 gene on chromosome 7, which encodes the type 2 muscarinic receptor as susceptibility genes for alcoholism (Dick et al, 2005), although it is not known if they contribute to the level of response to alcohol. In addition, animal studies have identified several other genes that alter acute responses to alcohol in rodents as candidates for the regulation of the level of response in humans (Schuckit et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Acute Functional Tolerance to Ethanol Mediated by Protein Kinase Cɛ

Wallace

Newton

Oyasu

et al. 2006

Neuropsychopharmacol

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A low level of response to ethanol is associated with increased risk of alcoholism. A major determinant of the level of response is the capacity to develop acute functional tolerance (AFT) to ethanol during a single drinking session. Mice lacking protein kinase C epsilon (PKCe) show increased signs of ethanol intoxication and reduced ethanol self-administration. Here, we report that AFT to the motorimpairing effects of ethanol is reduced in PKCe (À/À) mice when compared with wild-type littermates. In wild-type mice, in vivo ethanol exposure produced AFT that was accompanied by increased phosphorylation of PKCe and resistance of GABA A receptors to ethanol. In contrast, in PKCe (À/À) mice, GABA A receptor sensitivity to ethanol was unaltered by acute in vivo ethanol exposure. Both PKCe (À/À) and PKCe ( + / + ) mice developed robust chronic tolerance to ethanol, but the presence of chronic tolerance did not change ethanol preference drinking. These findings suggest that ethanol activates a PKCe signaling pathway that contributes to GABA A receptor resistance to ethanol and to AFT. AFT can be genetically dissociated from chronic tolerance, which is not regulated by PKCe and does not alter PKCe modulation of ethanol preference.

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The Search for Genes Contributing to the Low Level of Response to Alcohol: Patterns of Findings Across Studies

Cited by 145 publications

References 152 publications

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Voluntary ethanol consumption in 22 inbred mouse strains

Acute Functional Tolerance to Ethanol Mediated by Protein Kinase Cɛ

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