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5. Genetic Factors

Twin studies have estimated the heritability of smoking initiation and nicotine dependence to be >50% with estimates as high as 84% (Reich, Hinrichs, Culverhouse, & Bierut, 1999). Smoking initiation and subphenotypes, such as current smokers, heavy smokers, and nicotine-dependent individuals, are defined by thresholds on lifetime use (e.g., 100 cigarettes) and combined intensity and duration of use (e.g., >1 pack/day for >6 months).

In a study by Straub, Sullivan, Ma, Myakishev, Harris-Kerr, Wormley, and Kadambi (1999), 308 nicotine dependent subjects from New Zealand and a follow-up of 211 nicotine dependent subjects from the United States were assessed. This was a genomewide scan for linkage to nicotine dependence. The strongest findings were on chromosomes 2 and 10. The chromosome-2 peak was repeated in the replication sample, although the chromosome-10 peak failed to replicate. Smaller signals were detected on chromosomes 4, 16, 17, and 18.

The first genetic association studies in humans at dopaminergic loci were reported recently (Bergen & Caporaso, 1999). They found statistically significant differences in the allele frequencies between smokers and nonsmokers at markers linked to the genes coding for the D1, D2, and D4 dopamine receptors and at the dopamine transporter. This finding is consistent with the dopaminergic reward hypothesis of nicotine dependence.

Genetic epidemiological twin-study designs have estimated the effects of genetic and environmental factors on current smoking (Bergen & Caporaso, 1999). Multiple genetic and environmental risk factors and a threshold disease model are modeled by use of concordance data in monozygotic and dizygotic twins. In a reanalysis of seven twin studies from Scandinavia, the United States, and Australia, it was estimated that a mean of 60% of the variance in risk of being a current smoker in men and women is accounted for by additive genetic effects.

Most studies demonstrated statistically, non-significant shared environment effects. The same studies estimated the mean additive genetic effect on the liability to smoking initiation (becoming a smoker) to be 57% with an estimated mean shared environmental effect of 17%. Where data was available from three of the studies to assess the relative contributions to smoking persistence, the mean additive genetic effect was estimated to be 69%, with statistically non-significant estimated shared environmental effects.

Twin studies estimate that the majority of the liability to become and to remain a smoker is explained by additive genetic factors (Bergen & Caporaso, 1999). A recent analysis of smoking initiation and persistence among twin pairs in the Vietnam Era Twin Registry (True et al., 1997) found that the best-fitting model included statistically significant additive genetic factors (explaining 50% of variance in risk) and both shared (family, 30% of variance and specific (to one twin) environmental factors (20% of variance) for smoking initiation. For smoking persistence only genetic and specific environmental factors were statically significant, explaining approximately 70% and 30% of the variation, respectively.

Cigarette smoking is both comorbid with and genetically correlated with alcoholism (Reich, Hinrichs, Culverhouse, & Bierut, 1999). In a study by True, Xian, Scherrer, Madden, Bucholz, Heath et al. (1999), data from 3356 male twin-pair members of the Vietnam Era Twin Registry was analyzed. The data suggested a common genetic vulnerability to nicotine and alcohol dependence in men. This result may partially explain the clinical and epidemiological observations that alcoholics are often dependent smokers.

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