The Search for Genes Related to a Low‐Level Response to Alcohol Determined by Alcohol Challenges

Abstract

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.

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4

“…32 Several studies have not reported any significant linkage to this region of chromosome 4, including: a study of AD in multiplex families, 7 preliminary reports of AD samples collected in the UK 33 and Sweden, 34 a study of alcohol craving in the Mission Indian sample, 35 and two studies of ethanol response based on self-report among the initial COGA sample 36 and on physiological measures in a sib pair sample. 9 The latter study reported some evidence (LODs 1.3-1.4) for linkage to regions B40 cM away from our peak (at 60 and 180 cM) which could overlap with the region we identified given the wide confidence intervals surrounding linkage peaks. 37 Although the power of these studies to reject linkage is low, it is noteworthy that for only one of the six published samples has there been a linkage on chromosome 4 to AD diagnosis, 3 but for three there has been linkage to a severity or drinking volume phenotype.…”

“…7 Linkage analyses of drinking-related phenotypes have also been conducted using the Framingham Heart Study sample 8 and a sample of sib pairs ascertained in San Diego. 9 Overall, the regions implicated by these studies do not show a great deal of consistency, and the results are modest (e.g., LOD scores < 3.0). Possible contributing factors to this lack of consistency and the small effect sizes are low power as well as genetic and cultural heterogeneity among the US population samples and between the general population and Native American samples.…”

A genome wide search for alcoholism susceptibility genes

“…This marker is located within 3 cM of the cytochrome P450 (ethanol induced) gene (CYP2E). This region has previously been implicated in linkage analyses of the "low response to alcohol" phenotype seen in family history positive individuals in response to acute doses of alcohol (Subjective High Assessment Scale and body sway) [Wilhelmsen et al, 2003]. …”

Functional characterization of human variants of the mu-opioid receptor gene

“…The subjects used were from the San Diego Sibling Pair study (46,47), and consisted of college age students from the San Diego (mean ؎ SEM) for morphine and DAMGO in MOR1, MOR1A, A6V-MOR1A, S42T-MOR1A, S147C-MOR1A, or C192F-MOR1A metropolitan area. This collection was designed to identify families enriched for alcoholism susceptibility genes.…”