To outline the causes and consequences of alcohol‐related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene‐brain‐behavior framework. COGA is a family based, diverse (~25% self‐identified African American, ~52% female) sample, including data on 17,878 individuals, ages 7–97 years, in 2246 families of which a proportion are densely affected for AUD. All participants responded to questionnaires (e.g., personality) and the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA) which gathers information on psychiatric diagnoses, conditions and related behaviors (e.g., parental monitoring). In addition, 9871 individuals have brain function data from electroencephalogram (EEG) recordings while 12,009 individuals have been genotyped on genome‐wide association study (GWAS) arrays. A series of functional genomics studies examine the specific cellular and molecular mechanisms underlying AUD.

Alcohol Misuse Is Influenced by Environmental and Genetic Factors

Although studies in recent years have identified a plethora of genes that may play a role in determining risk of alcoholism, much work remains to be done. A failure to replicate the initial findings may not always disprove the association but may result from differences in the genetic background of the study participants, the environment, or the study design (e.g., differences in the definition of alcohol dependence). Beyond replication, the exploration of which specific aspects of the alcoholism phenotype each involved gene affects and which other diseases or traits may be influenced by it is essential.

There is evidence that heavy episodic (binge) drinking, which results inexposure of tissues to high levels of alcohol, is particularly harmful81, 87, 88. Binge drinkingis generally defined as a man consuming 5 standard drinks within 2 hours; women are typically smaller and have a lower percentage of body water, so 4 standarddrinks can reach similar alcohol levels. A standard drink is defined in the US as 12ounces of beer, 5 ounces of wine or 1.5 ounces of spirits, all of which approximate14 g of pure ethanol). The strong effects of binge drinking suggest that merelycalculating an average number of drinks per week is likely to obscure many effectsof alcohol, since it treats 2 standard is baclofen habit forming drinks per day (14 per week) the same as 7drinks on each of two days per week. The GI tract is exposed to very high levels of alcohol as it passes throughthe mouth, esophagus, stomach and intestinal tract, and most ethanol passes throughthe liver before entering the circulation.

Is Alcoholism Genetic? Understanding the Genetics of Alcoholism

Much additional work is required to narrow the regions and attempt to determine which specific gene or genes play a role in affecting the risk for alcoholism. Therefore, additional markers within these regions of interest were analyzed in the same people. Subsequent analyses that included the additional markers supported the initial findings (Foroud et al. 2000) but did not narrow the chromosomal regions in which genes influencing alcoholism susceptibility are likely to lie. If genetic influences or environmental factors shared by twin pairs growing up together are important, the percentage of twins of alcoholics with a current or past history of alcoholism should be much higher than the percentage in the general population.

Indeed, several strains of animals have been generated that display differences in alcohol-related behaviors, such as animals with high or low sensitivity to various effect of alcohol or with high or low preference for alcohol 104. Kerns et al. 121 studied differences in basal or ethanol-responsive gene expression in the brains of two strains of mice that differ markedly in a number of behavioral responses to ethanol. Several genes that were expressed differentially in the two strains as well as several ethanol-regulated genes were found within brain regions that are involved in reward, including the nucleus accumbens, pre-frontal cortex and ventral tegmental area. Tabakoff et al. 122 compared the mRNA expression profiles of mouse strains displaying marked differences in acute tolerance to alcohol and results from this study indicate the importance of a signal transduction cascade that involves the glutamatergic pathway.

Strategies for Identifying Genes Associated With Alcoholism Risk

Third, the combined genetic variability and family environmental contributions to alcoholism risk in the Iowa CFS and LSS studies total 100 percent, implying that nonshared environmental effects have no impact on alcoholism risk. As noted previously, alcoholism in adoptive families could include drinking problems that were caused by the behavior of the adoptee. Thus, the contributions of environmental and genetic variability would not be independent of each other.

Results of Genetic Analyses

1. So far, results appear to be particularly robust because of validation from different perspectives for MAOA and HTT.
2. Microarrays, often called gene chips, can be used to detect a person’s gene variants as well as variations in gene activity and to produce a series of medical, psychiatric and behavioral recommendations that the individual may take or leave as he or she wishes.
3. Abundant evidence indicates thatalcoholism is a complex genetic disease, with variations in a large number ofgenes affecting risk.
4. The power to examine patterns of inheritance in large populations, and to survey hundreds of thousands of tiny variations in the genomes of each of those individuals, enables investigators to pinpoint specific genes that exert strong or subtle influences on a person’s physiology and his or her resulting risk for disease.

One component of an ERP is a brain wave called P300, which typically occurs 300 milliseconds after a stimulus. Previous studies had found that a reduced amplitude of the P300 wave is a heritable phenotype that correlates with alcohol dependence and other psychiatric disorders (Porjesz et al. 1998). The genetic analyses of the COGA participants identified four regions, on chromosomes 2, 5, 6, and 13, that appear to contain genes affecting the amplitude of the P300 (Begleiter et al. 1998). Several study designs—including case–control studies, population studies, and family studies—have been used to test whether a specific gene or gene variant affects risk for a disease (for more information, see the article by Foroud and Phillips, pp. 266–272). For example, it is much easier to collect individual cases (i.e., people with alcoholism) and control subjects (i.e., nonalcoholic people) or samples of the general population than it is to recruit family samples. Moreover, family studies require more effort to determine the participants’ genetic makeup (i.e., genotype), because even with the simplest type of family study, genotypes must be determined for sets of three people (e.g., two parents and an affected child) rather than just for individual case and control subjects.

The researchers used biological parents who had no known histories of alcoholism but who also had given up a child for early adoption as control subjects. Interviews were conducted with adult sons and daughters of both groups to determine the prevalence of alcoholism among them. The researchers speculated that if the genetic contribution to alcoholism were important, the rates of alcoholism should be higher in the adopted-away offspring of the alcoholic biological parents than in the adopted-away offspring of the control parents. Insight, Not DestinyThe coga project has been structured around families, but this type of research has also strengthened understanding of the relative importance of specific gene variants as risk factors in different ethnic groups.