Offspring Studies in Alcohol Research Offer New Insight Into Comorbidity

Is the comorbidity of alcoholism and psychopathology strictly genetic in nature, or do environmental risk factors come into play as well? These issues were the focus of an invited address delivered by Andrew Heath, of Washington University School of Medicine, at the APS 15th Annual Convention in Atlanta. His talk, “Contributions of Genotype x Environment Interaction Effects to Psychiatric Comorbidity: Insights from Alcohol Research,” was sponsored by the National Institute on Alcohol Abuse and Alcoholism.

Heath, a Charter Member of APS, is the Spencer T. Olin Professor of Psychology in the Department of Psychiatry. In addition, he has appointments in the departments of Psychology and Genetics. His research is focused on understanding genetic and environmental contributions to the risk of psychiatric disorder, especially alcoholism and substance abuse, affective disorder, personality disorders and disorders of childhood and adolescence. He also investigates normal behavioral variation, such as personality, temperament, and smoking and drinking habits.

According to Heath, even when there is a clear link between the presence of a specific genotype and variations in alcohol consumption, it is also true that the importance of genetic influences may be greatly increased or decreased depending on the environmental conditions. Conversely, the effects of an environmental risk factor may be greatly increased in individuals with particular genotypes.

There are good reasons to expect that interactions between genotype and environment play a central role in alcoholism. In fact, it is difficult to separate the two. Individuals at high genetic risk also create high-risk environments for their genetic offspring and siblings. Parental alcoholism is a major predictor of high-risk environmental exposures from conception to adulthood, ranging from prenatal exposure to impaired parental supervision and heightened parent-child conflict. We also know that there is a high rate of comorbidity of alcoholism and conditions such as depression, drug dependence, anxiety disorders, personality disorders, and others. Do the interactions between genotype and environment put individuals at greater risk for alcoholism, and for the comorbidity of alcoholism and other disorders?

An obvious source in addressing these questions would seem to be twin studies and research involving adoptive families. Findings from both types of studies offer a “satisfying consistency” with regard to the role of heritability in behavior, said Heath. “Both suggest shared environmental influences associated with parental alcoholism are unimportant,” he noted, and “both suggest genetic transmission is the major determinant of familial resemblance for alcoholism.”

But this consistency may be misleading. Heath offered a number of caveats about both types of studies. For example, he noted that in studies involving adoptive children, it would be difficult to assess the interaction of genes and environment because adoptive parents tend to be older and less likely to be current alcoholics, and have lower rates of psychopathology, resulting in fewer cases of high-risk environmental exposures. It may also be the case, said Heath, that biological parents who give children up for adoption might have higher genetic risk factors, but information about psychopathology rates among biological parents is generally sketchy at best.

Adoption studies, said Heath “are useful in establishing that there is genetic transmission of alcoholism, but they are of limited value for characterizing that genetic transmission because of limited data about comorbid disorders in biological parents.” These studies also are of limited use in assessing the interaction between genes and environment in determining risk for psychopathology.

In twin studies, Heath said one confounding factor is that it is difficult to distinguish the interaction effects of genetics and environment for twins who are reared together.

These methodological problems may be mitigated though the use of inter-generational studies that look at the risk levels for the offspring of twins by gauging the alcohol dependence and psychopathology rates of both the parent and the parent’s co-twin. The advantages of the children-of-twins design are that the full range of high-risk environmental exposure is present (versus the more restricted exposures associated with adoptive parents) and there is no restriction in the range of genetic risk (versus the selection for more severe genetic risk in biological parents who give up a child for adoption). This design also allows researchers to look at the role of both parents.

The findings of several intergenerational studies, Heath said, “force us to reconsider” the importance of the effects of the interaction between genotype and shared environment effects in the etiology of alcohol use disorders.

This interaction also should be considered in research into the origins of the comorbidity between alcohol dependence and depression. Twins research has largely ignored the impact of environment on various genotypes, and Heath believes that the design of twins research can mask the effects of high-risk parental environmental influences, even though such effects may depend on the offspring’s genotype.

Other research has shown that people reporting early environmental trauma, such as childhood adversity, also report having alcoholic parents at a higher rate. Childhood adversity also is associated with increased risk of major depression and other psychopathology.

“Emerging data are now suggesting that genotype and environment interaction effects play an important role in determining alcoholism risk and the comorbidity of alcoholism with other disorders to a much great extent than we had previously suspected,” said Heath. “Children-of-twins designs offer us a new approach to investigate these interaction effects in the etiology of alcohol use disorders and their comorbidity with other psychiatric disorders.”