Indiana University School of Medicine researchers are learning more about the role genetics play in alcohol dependence, finding genetics and environment each play a role in a person’s risk of developing alcoholism.
“No one is genetically ‘destined’ for alcoholism,” said Howard Edenberg, PhD, a distinguished professor in the IU School of Medicine Department of Biochemistry and Molecular Biology and one of the study’s main authors. “We found there is no single gene for alcoholism. Many variants in many genes contribute, and the environment plays an equally important role.”
The study was carried out by a working group of the Psychiatric Genomics Consortium Use Disorder, a worldwide collaboration among many groups and individuals. It is the largest study to date that looks at risk genes of alcohol dependence. Below, Edenberg describes more about their findings and what they’re studying next.
Why was it important for this study to be completed?
This is the largest study to date that examines the entire genome in a search for risk genes of alcohol dependence as clinically defined. This was the first major effort of the Substance Use Disorders working group of the Psychiatric Genomics Consortium, a worldwide effort to understand the genetic basis for alcoholism and other substance use disorders. The idea is that better understanding can lead to improved and more personalized treatments, but we are not there yet. There are several treatments currently available for alcoholism, one of which works on the same metabolic process as the variants we found, but these are very early days. We need much larger samples and much more discovery in many more populations.
What makes this study different than previous studies on alcoholism?
There have been other gene-finding studies of typical alcohol use, such as drinks per week, but we are studying something quite different. Alcoholism is not just heavy drinking. People suffering from this serious illness have trouble controlling where, when and how much they drink, even when they are experiencing the many problems their drinking causes. Consistent with this idea, our study found the genetic susceptibility to alcohol consumption is only partially correlated with genetic risk for alcohol dependence. Some genes contribute to both, but others are likely to more specifically contribute to alcoholism.
What are some of the variations that can affect a person’s risk of alcoholism?
For many years now, we have known that different people process alcohol differently. The pace with which alcohol is converted to acetaldehyde is determined in part by differences in the alcohol dehydrogenase gene ADH1B. There are variations in ADH1B that speed up the conversion of alcohol to acetaldehyde, which can cause unpleasant reactions, such as nausea and flushing. That will generally reduce the chances that the person will drink heavily. Our study identified a strong protective effect of such variants on alcohol dependence. But despite being one of the strongest common genetic effects in psychiatry, these variants explain only a small portion of the overall genetic risk and a smaller proportion of overall risk. The results suggest many additional variants across the genome contribute to the risk of alcoholism, but their contributions are expected to be small, so very large sample sizes will be needed to identify them.
How do these genetic variations differ depending on a person’s race?
We found that even though the same ADH1B gene was important in individuals of European and African ancestry, the key variant in the gene was different. One variant is uncommon in Europeans and Africans, but relatively common in some Asian populations. Another variant is relatively common in Africans, but rare in others. Thus, while the mechanism that affects risk is similar between populations, the specific genetic variants that affect risk can differ. This has important implications for risk prediction and personalized treatment. To know about the genetics in a population, you have to study that population. More studies in more populations are important to better understand this and other disorders and lay the groundwork for better prevention and treatment that serve that specific population.
How much does the environment play a role in a person’s risk of alcoholism?
We should remember that even the strong effects of genes like ADH1B are modified by the environment. Individuals with the so-called “protective allele” might drink when they are surrounded by friends who drink, and those without the protective allele may be more likely to experience drinking problems in the context of lifetime trauma. While ADH1B and other genes can provide some limited insights into who might be at risk, whether or not someone develops alcoholism is the result of a complex network of genetic and environmental factors.
Our study also found susceptibility to alcohol dependence was correlated with genetic susceptibility to other psychiatric illnesses, such as depression, cigarette smoking or drug use, and behavior traits, such as higher neuroticism (which often leads to feeling anxious or depressed) or lower overall well-being. As studies get larger, we may be able to determine how much of this correlation is indicative of alcoholism being the cause or consequence of these other disorders.
What research on alcoholism do you hope to complete in the future?
As I said, to learn more about this devastating disorder, we will need much larger studies and studies that include many more populations around the world. We are working toward assembling such studies and encouraging others to begin studying more populations. When we have discovered more genes that affect risk, the next step will be to study the mechanism through which they work, and that might lead to new treatments and better matching of individuals to a treatment more likely to work for them. We are in this study for the long term.