Large Twin Study Suggests Distinct Genetic Influences in Legal vs Illicit Drug Dependence

Jacquelyn K. Beals, PhD

November 09, 2007

November 9, 2007 — A new study surveying drug dependence among same-sex twin pairs has found that best-fit models contain separate genetic factors for legal and illicit drug dependence. Published in the November issue of the Archives of General Psychiatry, the study also confirmed the lack of sex differences previously observed in studies involving only nicotine or cannabis dependence.

Lead author Kenneth S. Kendler, MD, distinguished professor, Departments of Psychiatry and Human Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University; director, Psychiatric Genetics Research Program; and director, Virginia Institute for Psychiatric and Behavioral Genetics, all in Richmond, commented via email to Medscape Pathology about the substances selected for this analysis: "We chose the 3 legal psychoactive drugs in our society and the 2 most common illicit substances," he explained.

Although some of his previous publications have dealt with sedatives, opiates, and hallucinogens, Dr. Kendler noted that "rates of sedative and opiate abuse in females were too low to meaningful[ly] analyze." Thus, this study investigated the illicit drugs cannabis and cocaine and the licit drugs alcohol, caffeine, and nicotine.

Participants were same-sex twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Women were born between 1934 and 1974, men between 1940 and 1974. Of the twins, 1666 male twins were monozygotic (identical) and 1269 dizygotic (fraternal); 1151 female twins were monozygotic and 779 dizygotic.

Participants' substance abuse/dependence history was obtained from several interviews. Psychoactive drug dependence was expressed in ordinal measures, with measures of cocaine, cannabis, and alcohol abuse/dependence derived from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ( DSM-IV). Data on substance abuse/dependence were not complete for every subject.

"For alcohol, we divided all subjects into 4 categories: those meeting...criteria for abuse or dependence. For cocaine abuse/dependence — owing to the rarity of those endorsing 5 or more symptoms — we divided subjects into only 3 categories," the study reports. The investigators assessed nicotine dependence with the Fagerstrom Test for Nicotine Dependence, with subjects reporting their heaviest use of tobacco. Assessment of caffeine dependence included symptoms of withdrawal and tolerance, both based on the DSM-IV.

Correlations between ordinal measures of symptoms of abuse/dependence were highest for the 2 illicit substances, cannabis and cocaine (0.76 in both male–male and female–female pairs; P < .001). Other correlations in men were alcohol–cocaine (0.58; P < .001) and alcohol–cannabis (0.54; P < .001). In women, correlations were alcohol–cocaine (0.66; P < .001), alcohol–cannabis (0.57; P < .001), and nicotine–cannabis (0.52; P < .001). Other measures demonstrated significant, but lower, levels of correlation. Caffeine dependence had low correlation with all other substance dependencies assessed.

Models were based on 3 factors: genetic effects, shared family environment, and unique environment. The best-fitting model contained 2 genetic factors and 1 factor based on unique environment that affected all substances. Cocaine and cannabis dependence were closely associated with the first genetic factor, whereas nicotine and alcohol dependence related to a second genetic factor. In addition, substance-specific genetic effects were indicated for both nicotine and caffeine.

A second good-fitting model contained 1 genetic factor associated with cannabis and cocaine (illicit) and 1 genetic factor related to alcohol, caffeine, and nicotine (licit). Nicotine and caffeine dependence again involved substance-specific genetic effects.

Medscape Pathology also talked with David Goldman, MD, section chief, human neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland: "What's so fascinating about this result is the finding that there is substantial sharing of vulnerability across substances, but that these 2 broad groups break out as a bit individual — the licit and illicit. And of course the different substances that are in the licit group are not coherent in their actions, and neither are the substances that are in the illicit group."

Dr. Goldman continued, "What that's saying is that at least some of the genetic factors that are underlying vulnerability are interfacing with our ability to control behavior."

The study reached 3 conclusions:

  • After controlling for the higher dependence rates among men (for all 5 substances), "the pattern of comorbidity between licit and common illicit substance dependence" did not differ with sex;

  • The genetic risk of dependence cannot be explained by 1 genetic factor: Both well-fitting models contain 2 genetic factors, as well as indicating substance-specific genetic effects for nicotine and caffeine; and

  • The second model proposes 1 genetic factor for illicit and 1 factor for licit drug dependence, although substance-specific genetic effects were again indicated for nicotine and caffeine.

Dr. Kendler confirmed that the chemical structures of the drugs do not correlate with the dependence/abuse patterns in individuals. As the report explains, "These results are not consistent with the hypothesis that most genetic variation that influences risk for dependence in humans occurs in the primary sites of action of the psychoactive drugs themselves."

Dr. Goldman offered further comments: "There are genes that are being tied to both of these dimensions of behavior — both the internalizing [eg, anxiety and dysphoric disorders, and to some extent addictions] and the externalizing [eg, problems of cognitive control] dimension.

"The functional alleles that have been tied to externalizing behavior — a good example would be the monoamine oxidase A polymorphism, and a very good example of a functional polymorphism that has been tied to the internalizing dimension would be the serotonin transporter promoter polymorphism." He noted that the broader quantitative description is very crucial, but "things are moving forward beyond that, to the level of the actual genes that are responsible for these inherited variations."

In terms of gene finding, the study indicated that any search for a genetic basis for caffeine dependence should focus on substance-specific factors, and the same is probably true for nicotine dependence. However, the models suggest that several genes may influence the tendency for dependence on licit vs illicit substances. Whether this difference relates to biological processes or to behavioral characteristics has yet to be resolved.

Dr. Kendler and Dr. Goldman have disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2007;64(11):1313–1320.

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