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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.

Suppression of serum GH levels in immature rats is associated with delayed onset of puberty and decreased ovarian steroidogenic responsiveness to FSH. To investigate possible direct effects of GH on the differentiation of ovarian cells, granulosa cells from hypophysectomized estrogen-treated rats were cultured with FSH in the presence or absence of GH for 3 days. FSH stimulated granulosa cell LH receptor formation and steroid production in a dose-dependent manner. Concomitant treatment with GH increased LH receptor content by enhancing the action of low doses of FSH without substantial increases in the maximal response. This increase was due to an elevation in the receptor number rather than changes in their affinity for hCG. At 3 ng/ml FSH, concomitant treatment with ovine or bovine GH increased LH/hCG binding in a dose-dependent manner, with 300 ng/ml GH increasing the FSH action by about 3-fold. LH receptors in the GH-treated cells were functional, as indicated by the enhanced cAMP production of these cells in response to LH treatment. The cellular protein content in the FSH-treated cultures was slightly increased by GH (18%), but cell number and viability were unaffected. The change in cell protein content could not account for the increases in the amount of LH receptors. In addition to its effects on LH/hCG receptor content, GH also augmented FSH-stimulated progesterone and 20 alpha-hydroxy-4-pregnen-3-one production in a dose-dependent manner, with 100 ng/ml GH causing significant increases in FSH-induced progesterone production. In contrast, GH treatment did not significantly affect FSH-stimulated estrogen production. The augmentating effects of GH on LH receptor formation and progestin biosynthesis were associated with an enhancement of FSH-stimulated cAMP production. In addition, GH increased forskolin- and 8-bromo-cAMP-induced LH receptor formation and progestin production. Thus, GH-augmented LH receptor induction and progestin biosynthesis may be due to both increased cAMP production and enhanced action of cAMP. The present data have demonstrated that GH augments gonadotropin-stimulated differentiation of ovarian granulosa cells, suggesting an important regulatory role of GH in follicular growth and pubertal development.

Case reports and laboratory research indicate the existence of a cannabis withdrawal syndrome. However, the data tell us little about the prevalence and clinical characteristics of a marijuana withdrawal syndrome in people who have used the drug but who did not enter treatment for cannabis dependence. Face-to-face semi-structured interviews applying standard diagnostic criteria were used in the present study to gather data from 5611 men and women, recruited between 1991 and 1995 through the Collaborative Study of the Genetics of Alcoholism (COGA). Almost 41% of the sample had no history of marijuana use (Group 1), 28% had consumed this drug less than 21 times in any single year (Group 2), and 31% used it at least that frequently (Groups 3 and 4). Almost 16% of the more frequent marijuana users related a history of a marijuana withdrawal syndrome, and these Group 4 subjects had used the drug almost daily for an average of almost 70 months. The typical withdrawal symptoms included "nervous, tense, restlessness", "sleep disturbance" and "appetite change". While Group 4 subjects were more likely to have developed dependence on most types of drugs, even when alcohol and drug use patterns were statistically taken into account, marijuana use was still significantly related to a self-report of a history of marijuana withdrawal.

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)....

These evaluations from the largest known alcohol challenge-based genetic study to date highlight the potential importance of genes on chromosome 10 as possible contributors to the low LR to alcohol as a risk factor for alcoholism.