We attempted to address three major questions in these analyses: (i) does shared genetic and/or environmental liability contribute to the correlation between MD and tobacco use?; (ii) does the structure of genetic and environmental influences differ across the sexes?; and (iii) among males, does this structure differ depending on the type of tobacco used?
Our results support the hypothesis that MD, regular tobacco use and ND share a common liability. In males, the nature of the non-causal relationship between MD and regular tobacco use – for both cigarettes and snus – can be accounted for entirely by genetic factors shared by these traits. In females, genetic and environmental influences contribute to this covariance. Estimates of the genetic correlation between MD and regular tobacco use or ND are modest, ranging from ra = 0.13 to 0.30, indicating that the genetic liability to these traits is largely specific to each. However, genetic correlations are higher than environmental correlations (re = 0–0.17).
A summary of previous reports of genetic correlations between MD and tobacco use traits is provided in . Our estimate of the genetic correlation between MD and regular smoking in females is substantially lower than has been previously reported in adult (Kendler et al. 1993
) and adolescent (McCaffery et al. 2008
) females. Our results for males are comparable with (but lower than) other reports of genetic correlations between MD and regular smoking. Our estimate of the genetic correlation between MD and cigarette-based ND is substantially lower than that reported by Lyons et al. (2008)
. This discrepancy may be partially attributable to their use of a dichotomous rating of ND, whereas the current report used five categories of dependence derived from the FTND; these scales might measure different aspects of ND (Hughes et al. 2004
; Kandel et al. 2005
Summary of previous reports of genetic correlations between depression and tobacco use
Given the consistency in heritability estimates of MD across samples, and the likelihood that the genetic basis of ND – that is, which is specific to dependence rather than shared by initiation or regular use – is unlikely to be substantially different across populations, the high phenotypic correlations and modest genetic correlations between these traits suggest that social factors heavily influence smoking behavior. These social factors – and the genes influencing them – likely differ across countries, cultures and cohorts.
We detected significant sex differences for ND. Among cigarette smokers, ND was more highly heritable among women (a2 = 0.62) than men (a2 = 0.48). Furthermore, the proportion of genetic effects specific to ND – that is not shared with depression or regular use – was much greater in males (about 80%) than in females (49%). For both sexes, the remaining variance is shared mostly with regular cigarette use, and only a modest amount of the total genetic variance in ND is shared with depression. The difference between sexes in the proportion of ND-specific genetic effects is due mostly to the β path: for women, regular smoking and ND exhibit relatively high continuity, whereas additional, unidentified factors are relevant for men.
In general, our estimates for the heritability of regular smoking and cigarette-based ND are comparable with those from the Virginia Twin Registry (a2
= 0.80 for regular use and 0.67 for ND) (Maes et al. 2004
), although in that sample variance could be constrained to be equal across the sexes. Heritability specific to dependence is also similar across the studies (a2
= 0.26 for the Virginia sample v
. 0.37 for Swedish males and 0.30 for Swedish females).
A notable difference between these studies is in the continuity between regular smoking and subsequent ND. In contrast to our results, Maes et al. (2004)
found that this parameter approached unity (β
= 0.93). This difference is particularly striking among males in the current study (β
= 0.37). Lyons et al. (2008)
reported an intermediate result (β
= 0.54) among men. An analysis of the pathway from smoking initiation to ND in female twins (Kendler et al. 1999
) estimated the β
path to be similar to that reported here for females (β
= 0.77, v
. 0.63 in the current study). Swedish males appear to be outliers in that the sources of variance influencing regular cigarette use are only modestly influential on ND. The causes underlying this deviation from previous results are unclear.
In our male sample, we sought to compare the genetic and environmental influences on cigarette use and snus use, as well as on ND as associated separately with these two different tobacco products. The heritabilities of regular snus use and regular cigarette use are similar; however, snus-based ND is more highly heritable, and the relationship between regular snus use and ND (i.e. the β path) is stronger than that between regular smoking and ND. Accordingly, relative to regular smoking and cigarette-based ND, far more of the total genetic variance of snus-based ND is shared with regular snus use (20% v. 57%, respectively). Furthermore, although the differences are modest, it is worth noting that the genetic correlation between MD and RUS (ra = 0.22) is higher than between MD and RUC (ra = 0.13), indicating that the genetic liability shared between MD and tobacco use is higher for this less common method of tobacco administration than for cigarette smoking.
Few studies have examined the relationship between MD and smokeless tobacco use. Sihvola et al. (2008)
explored early (age 14 years) depressive disorders and later (age 17.5 years) cigarette use or smokeless tobacco use in a Finnish population, and found similar odds ratios for both types of tobacco use. Those findings are generally in agreement with our own. Schmitt et al. (2005)
investigated cigarette and smokeless tobacco use in the male sample of the Virginia twin study and reported heritability estimates similar to those reported here for both regular cigarette use (a2
= 0.69 for males in the current study versus
0.64 by Schmitt et al
.) and snus use (a2
= 0.66 v
Potentially relevant differences among samples include ethnicity, age and culture. Some evidence suggests that heritability increases in the context of permissive environments, such as increased acceptance of smoking among women in younger populations (Kendler et al. 2000
), although this is not always the case (Kendler et al. 2004
). We conducted post-hoc
analyses to assess the extent to which heritability differed by cohort by dividing our sample into two using a median split by birth year. The resulting heritability estimates were quite similar in both groups (data not shown), though this does not preclude the possibility that cohort differences are contributing to the discrepant results across samples. Overall, our estimates of the heritabilities of these traits are comparable with previous reports.
Although shared genetic and environmental liabilities influence MD, regular tobacco use and ND, causal pathways might also contribute to the association among these traits. The details of causal hypotheses and how they might apply to our results are beyond the scope of this study. Briefly, evidence suggests that nicotine can have detrimental effects on neurotransmitter systems and neural integrity (e.g. white-matter lesions) (Ding et al. 2003
; Malone et al. 2003
), which could in turn have an impact on depressive symptoms (Balfour & Ridley; 2000
; Tiemeier, 2003
). Alternatively, individuals experiencing depressed mood might use nicotine as a form of self-medication (Parrott, 2006
), in which case depressive symptoms could lead to tobacco use rather than vice versa.
To our knowledge, this is the only study that includes MD, regular tobacco use and ND, while accounting for the conditional nature of ND on tobacco use, in a single structural equation model. This design enables us to partition the genetic and environmental influences on ND into those that are ND-specific versus shared only with regular tobacco use, shared only with MD, or common to all three traits. Furthermore, we are able to compare these influences across the sexes, as well as between different types of tobacco use among males. Both the genetic and environmental components of this shared risk are modest, with genetic correlations slightly higher. These findings have potential clinical implications, in that individuals who regularly use cigarettes and/or snus might be at an increased risk for MD due to shared liability in addition to risk due to causal relationships among phenotypes. Furthermore, these results could be informative for gene-finding efforts, including genome-wide studies, since variants associated with a phenotype such as MD could be considered candidates for ND or regular tobacco use as well. Considered in the context of varied estimates of genetic correlation across sexes, cultures and cohorts, our results are consistent with the hypothesis that MD, tobacco use and ND share a statistically significant genetic and/or environmental liability, but do not preclude the existence of causal factors.
These results should be considered in light of a number of limitations. First, our sample was limited to Swedish individuals, and the generalizability of these results to other populations is not known. Second, our measures of ND did not take into consideration the fact that many individuals use both cigarettes and snus, and could thus have higher levels of ND than they were assigned in these analyses. However, post-hoc analyses suggest that, among individuals who use both types of tobacco, few would be classified as having a different level of ND had we employed a more global assessment of dependence. Third, our data were cross-sectional and retrospective, and may be subject to errors in recall.
Fourth, our analyses assumed that the exposure to etiologically relevant environmental risk factors is equally correlated in monozygotic and dizygotic twin pairs. Concordance for cigarette-based ND was significantly predicted by our measure of childhood environment. How this environment might influence ND concordance is unclear, particularly given that it was not predictive of concordance for regular use of tobacco which we considered more likely to be influenced by social factors. The measure accounted for only a very small proportion of the total variance, and is within the CIs of our estimates. Therefore, we feel that it is unlikely to have introduced significant biases in our results. Finally, these analyses were not corrected for potentially confounding factors, such as other types of psychopathology, neuroticism or socio-economic status.