General background about how genes contribute to alcohol use disorder risks:
The pattern of causes of alcohol use disorders are typical of most diseases such as heart attacks and diabetes in that genes contribute to the risk in the context of the environment and a person’s opinions and attitudes (e.g., Schuckit et al., 2011, 2012b). The genetic influences for these conditions don’t follow the rules for dominant and recessive disorders that apply to relatively rare conditions where a change (variation or mutation) in 1 or only a few genes directly cause the disorder, as is seen for Cystic Fibrosis or Huntington’s Disease. Most genetically influenced conditions, including alcohol use disorders, develop through a small impact by many different gene variations that interact with a person’s environment and attitudes.
Because so many different genes and such a wide range of environmental and attitudinal characteristics contribute to the risk for an alcohol use disorder it is difficult to find major genetic “causes” if a research study focuses on the very broad concept of the diagnosis itself. An example of this problem can be seen with heart attacks. About 40% of the risk for heart attacks comes from genes, and the rest comes from the environment (for example, eating fatty foods) and attitudes (such as thinking exercise is not important), as well as their interaction with genes. So, it is unlikely that there is a “heart attack gene” waiting to be discovered. Rather, the risk for heart attacks comes indirectly from many different sets of genes some of which contribute to high blood pressure, other genes that contribute to high “bad” (low density lipoprotein) cholesterol (LDLs), and yet others that contribute to a vulnerability to develop a deterioration of heart muscle tissue, with each of these interrelating with environment and attitudes. The optimal search for genes related to heart attacks might focus on genes for each risk factor.
The genetic influences in alcohol use disorders operate through a range of different genes. Some gene effects are related to the protective impact of variations in some of the proteins that break down (metabolize) alcohol in the body, as described in other sections of the COGA website. These gene variations impact on the development of heavy drinking and problems related to alcohol, but have almost no effect of the use and problems with other drugs. Other gene variations increase the risk for being impulsive (that is, a tendency to make decisions on the spur of the moment and without considering the consequences) and yet others operate to increase the likelihood of developing any of several psychiatric disorders such as schizophrenia or bipolar (manic depressive) disorders. How a person responds to alcohol is another important genetically influenced characteristic that adds to the risk for multiple alcohol problems.
How a person’s intensity of response to alcohol operates
People vary in intensity of response to alcohol, and this is another genetically influenced characteristic that impacts risk for alcohol use disorder. A low response to alcohol is evident early in some people’s drinking career and increases the risk for alcohol use disorders but not for problems with other drugs. The higher the number of drinks required to get a desired effect, the greater the number of drinks a person is likely to consume per occasion. As explained in more detail below, the need for higher doses of alcohol to get desired effects contributes to selecting heavy drinking friends, attitudes that heavy drinking is a good way to have fun, and to the tendency to use alcohol to help deal with problems. Taken together this pattern creates a gene/environment/attitude model of the risk for alcohol use disorders, one that is different from models that apply to the higher risk for problems with alcohol and other drugs due to greater impulsivity and the impact of other psychiatric conditions.
The importance of a person’s low level of response (low LR) to alcohol was originally discovered by comparing 20-year-old drinkers at higher risk for the future development of alcohol problems (based on their report of having an “alcoholic” parent) with lower risk drinkers who had no relatives with alcohol use disorders. Everyone in this study took part in a laboratory session where they drank the same amount of alcohol (adjusted for their height and weight) and their reactions to the alcohol were evaluated at similar blood alcohol levels as those levels changed over 3 hours. The group who had relatives with alcohol use disorders showed less alcohol related changes in several measures including alterations in brain waves, coordination, balance, and feelings of intoxication than the group with no parents with severe alcohol problems.
Giving people alcohol and measuring the alcohol-related changes (alcohol challenges) is a valid way to identify people with a low alcohol response, but it is expensive and requires almost a full day of testing. As a result, relatively few people can be evaluated. In response to this limitation, COGA was instrumental in developing a simple 5-minute questionnaire where drinkers give information about their usual intensity of alcohol responses by reporting their histories of the number of drinks usually required for up to 4 different effects using the Self Report of the Effects of Alcohol (SRE) questionnaire. Using the SRE, the need for a higher number of drinks for effects means that there is a lower response per drink, which is similar to feeling less effect at a specific blood alcohol level during an alcohol challenge in the laboratory.
Because COGA evaluates participants over time (it is a prospective study) our group has been able to evaluate if a low level of response to alcohol predicts future increases in alcohol quantities and higher rates of future alcohol problems. Follow ups of COGA participants have consistently shown that younger drinkers who were originally evaluated before they developed an alcohol use disorder and who demonstrated a low response per drink were at least twice as likely to develop an alcohol use disorder compared to individuals with a higher response per drink. This increased risk was true even after considering the person’s usual drinking quantities and frequencies and their family histories of alcohol problems. Similar findings have been reported in most other studies.
Our group has also been interested in how environment and attitudes relate to the intensity of alcohol responses in predicting future alcohol problems. Studies in both the original COGA subjects and in the next generation of these families have highlighted the importance of several of these characteristics. While there are some differences in how well this model applies across older versus younger participants and across males and females, here is a general description of the results. The prospective studies in COGA indicate that having a low response per drink and living in a relatively heavy drinking society like the United States makes it more likely a person will choose and be chosen by heavy drinking friends who encourage the heavy drinking per occasion that originally developed from your low alcohol response. Then, the combination of a low response and heavy drinking friends contribute to developing the belief that one situation where a person can really enjoy themselves is when they drink heavily. Subsequently, the heavier drinking is likely to contribute to feelings of depression and interpersonal problems with relatives and friends, where the person is likely to turn to alcohol to cope with stressful situations, many of which might developed as a result of heavy drinking in the first place. This model has also been observed in a 35-year prospective study in San Diego and in a study of 8000 young adults who had been followed since birth in the United Kingdom. A recent study that reflected what we have learned in COGA showed that teaching this model to drinking college students who have a low alcohol response per drink was associated with subsequent decreases in heavy drinking and alcohol problems over the next year.
Finally, because thousands of people can fill out the SRE at very little cost, the questionnaire has been used to search for what is likely to be many genes that contribute a small amounts to the risk for the low alcohol response. Studies by COGA and other groups have identified gene variations that might contribute through a wide range of brain chemical systems that are affected by alcohol. These include systems that operate at least in part through the effects of serotonin, acetylcholine, gamma-aminobutyric acid, and dopamine, to name only a few. Much more work is needed to verify these tentative findings, work that is underway as an important part of COGA as time moves forward.
*Note that the material presented here was extracted from several published papers. These include Schuckit M A (2014) A brief history of research on the genetics of alcohol and other drug use disorders. J Studies on Alcohol and Drugs Supplement 17: 59-67 and Schuckit M A (2018) A critical review of methods and results in the search for genetic contributors to alcohol sensitivity. Alc:Clin Exper Research 42(5): 822-835.
