Twin Studies to Understand Comorbidity: The Case of Cannabis Use Disorder

Psychiatric patients usually meet diagnostic criteria for more than one disorder. Such “comorbidity” always raises questions of what causes what, for if one problem underlies the other, clinicians can hope that treating the first will resolve both. Although in practice problems tend to have lives of their own and require their own treatments, an understanding of how patients’ disorders relate to each other provides an explanatory narrative for patients and clinicians as they consider their options.

Arpana Agrawal, a geneticist at Washington University, and Michael Lynskey, who studies addiction at King’s College London, have described several genetic approaches to the co-occurrence of cannabis use disorder with other psychiatric disorders. Their work is interesting because it extends methods of genetic analysis which have clarified the heritability of numerous psychiatric disorders to the field of comorbidity. They begin with twin studies and go on to look at research on particular gene variants; in this post I will discuss their twin research.

In principle, two disorders may occur together because the first causes the second, because the second causes the first, or because a third factor causes both. The third factor might be a genetic abnormality or something in the environment. An additional possibility is that one disorder causes the other only in the presence of an additional factor, which could be genetic or environmental. This conceptual framework is obviously a simplification: it is likely that a plethora genetic, epigenetic, and environmental factors underlie most psychiatric phenomena, but it is a starting point for sorting things out.

Monozygotic twins share the same genes, and any discordance for cannabis use disorder must be due to differences in personal environmental exposures. To evaluate comorbidity (Here Agrawal and Lynskey use the example of comorbidity with “hard” drug use disorders), one looks only at monozygotic twin pairs discordant for cannabis use disorder. If only those with cannabis use disorder tend to have another disorder, then the comorbidity cannot be due to shared genes. (There is an “equal environments assumption,” i.e. that twins reared together share the same family environment, which cannot be fully valid.) The possibilities include socio-environmental factors, pharmacological factors such as cannabis sensitizing the brain’s addiction circuits to other drugs, and epigenetic modifications. (I hope to write about psychiatric epigenetics in another post.)

The authors go on to describe another twin study approach which compares the frequency of comorbidity in monozygotic twins, dizygotic twins, and unrelated individuals. If extra-familial environmental factors are the sole cause of an association between two disorders, the three groups should have the same rate of comorbidity. To the extent that genes contribute, monozygotic twins will have the highest, dizygotic twins intermediate, and unrelated individuals the lowest rates of comorbidity. If comorbidity is entirely due to family environment, both groups of twins will have the same higher rates of comorbidity, with unrelated individuals lower. And if comorbidity requires both shared genetic vulnerability and an environmental factor, the rates of comorbidity for the groups will fall between those for genetics alone and environment alone.

Agrawal and Lynskey cite studies of four different twin samples by their group and one by another group, all of which found elevated rates of hard drug use in marijuana-using twins compared to their co-twins that did not use marijuana. The finding persisted after controlling for tobacco and early alcohol use, conduct disorder, major depression, and social anxiety, as well as in a Dutch sample, where marijuana was legal. This means shared genetic factors are unlikely to cause the well-established association between marijuana use and hard drug use, and the association must be due to person-specific environmental factors or to pharmacological sensitization to hard drug addiction by marijuana. However, they note an alternative explanation: that the association is due to the natural development of substance abuse, which is genetically influenced. This last would be an example of a gene-environment interaction—comorbidity would require both genetic susceptibility to progressive addiction and environmental exposure to marijuana.

What is new here is the extension of twin study genetics from analyzing frequencies of disorders in samples of various degrees of genetic relatedness to comparing rates of comorbidity. As with the frequency studies, this type of analysis can only estimate genetic contributions and, with the exception of the shared family environment of monozygotic and dizygotic twins, is incapable of distinguishing different types of environmental and pharmacological effects.

Further Reading:

Agrawal A, Lynskey MT, Cannabis controversies: how genetics can inform the study of comorbidity. Addiction 2014; 109:360-370.

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