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Background:The low level of response (LR) to alcohol is genetically influenced in both humans and animals, and a low LR is a characteristic of offspring of alcoholics that has been reported to predict alcoholism 10 and 15 years later. The genes that contribute to a low LR have not yet been identified.Methods: A 12-item questionnaire that measures LR, the Self Rating of the Effects of Alcohol (SRE) instrument, was filled out by 745 individuals from the Collaborative Study on the Genetics of Alcoholism (COGA) for whom genetic material was available. These subjects were genotyped by using 336 markers with an average heterozygosity of 0.74 and an average intermarker distance of 10.5 cM. Both quantitative and qualitative nonparametric, sib-pair analyses were carried out for the SRE measure related to early drinking experiences.Results: Correlations of SRE scores across related individuals were significant and between 0.16 and 0.22 for most values, compared with nonsignificant correlations of 0.03 or less among unrelated individuals. Linkage analyses performed by using the FIRST 5 variables (first five times alcohol is consumed) identified four chromosomal regions with lod scores Ն2.0 whose maximum was also near a marker. One of these chromosomal regions previously was linked to alcohol dependence in the COGA sample.Conclusions: These data document the familial nature of a low LR to alcohol as measured by the SRE and suggest several chromosomal regions that might contribute to the phenomenon.

The review identifies several genes that may contribute to a low LR to alcohol and, thus, to an increased risk for alcohol use disorders. The chromosomal regions and genes highlighted here may form the basis for more focused genetic studies of alcohol use disorders, with the goals of developing more specific and effective prevention and treatment approaches.

Background: A low level of response (LR) to alcohol seems to relate to a substantial proportion of the risk for alcoholism and to have significant heritability.Methods: This report describes the results of a genome-wide segregation analysis for the first 139 pairs of full siblings by using an alcohol challenge protocol as a direct measure of LR. Subjects from 18 to 29 years old were selected if the original screen indicated they had an alcohol-dependent parent, reported a personal history of drinking but had no evidence of alcohol dependence, and had a full sibling with similar characteristics. Body sway and Subjective High Assessment Scale scores were measured at baseline and at regular intervals after the administration of a measured dose of alcohol. Participants and available parents were genotyped for 811 microsatellite markers, and resulting data were analyzed with a variance component method.Results: Nine chromosome regions with logarithm of the odds ratio (LOD) between 2.2 and 3.2 were identified; several had previously been implicated regarding phenotypes relevant to alcoholism and the LR to alcohol. Several regions identified in the previous linkage study by using a retrospective self-report questionnaire were potentially confirmed by this study. The strongest evidence was on chromosomes 10, 11, and 22.Conclusions: Several chromosomal areas seem to relate to the low LR to alcohol as a risk factor for alcohol dependence.