Smoking as a Cause of Depression

Adolescent smoking is a major public health problem, yet much remains to be learned about why some adolescents progress from smoking experimentation to regular smoking while others do not. Individual differences in genetic susceptibility may account, in part, for the variability in rates of adolescent smoking and progression. There is abundant evidence for the heritability of smoking initiation, age at smoking onset, and smoking persistence (1ЁC4). Heritable predisposition to smoking may be mediated, in part, by genetic variation in the dopamine pathway (5). Support for this hypothesis has emerged from studies linking smoking behavior with the more rare A1 and B1 alleles of the gene for the dopamine 2 receptor (DRD2) (6ЁC8) and the 10-repeat allele of the dopamine transporter gene (SLC6A3) (9, 10) in adults. However, these findings have not been replicated in all cases (11ЁC13). The 9-repeat allele of SLC6A3 has also been associated with a 22% reduction in dopamine transporter protein, resulting in less clearance and greater bioavailability of dopamine (14). Thus, it is possible that individuals who carry the other common allele of SLC6A3, the 10-repeat allele, may achieve greater reward from nicotineЎЇs effects on dopamine activity.

Although these genetic association studies have provided preliminary evidence for specific genetic effects on smoking practices, they have several limitations. For example, case-control designs have been criticized for not accounting for the potential biasing effects of ethnic admixture (i.e., cases and control subjects may have been drawn from populations with different ethnic ancestries) (5, 15). A second limitation of previous research has been small subject groups, which may have affected the ability to detect associations with genes having small effects (16). In addition, previous research has relied on general assessments of smoking status (e.g., smokers versus nonsmokers). Given the complex nature of smoking behavior and its etiology, it is critical that the phenotypes for genetic studies of smoking be well defined (17). Finally, there has been a lack of attention to adolescent populations in research evaluating genetic contributions to smoking behavior. The genes involved in smoking experimentation and acquisition of a habit during adolescence may be different from those that maintain a smoking habit or explain nicotine dependence in adulthood.

Another gap in our understanding relates to the interactions of genes with other factors that have been shown to increase adolescent vulnerability to smoking. For example, depression appears to be an important factor in adolescent smoking (18ЁC20). Evidence exists to suggest that there may be common influences, possibly genetic, on both depression and smoking (21, 22). Depression symptoms have also been shown to moderate the effects of dopaminergic genes on smoking practices (23). To generate new knowledge about the biobehavioral basis of adolescent smoking, the present study evaluated the Am J Psychiatry 161:7, July 2004 1225 AUDRAIN-McGOVERN, LERMAN, WILEYTO, ET AL. http://ajp.psychiatryonline.org effects of polymorphisms in SLC6A3 and DRD2 on smoking practices and smoking progression in a large cohort of 615 high school adolescents of European ancestry who were followed from 9th grade to 11th grade. We hypothesized that adolescents with DRD2 A1 and/or SLC6A3 10-repeat alleles who had an initial biological exposure to nicotine (i.e., had smoked at least a puff) would be more likely to progress to higher levels of smoking over the 2 years of longitudinal follow-up. We further hypothesized that genetic effects on smoking practices would be potentiated by depression symptoms, as measured by the Center for Epidemiological Studies Depression Scale (CES-D Scale) (24). Finally, we did not expect to find significant effects of DRD2 and SLC6A3 on smoking initiation (i.e., progression from never to ever) because students who had never smoked would not have had the opportunity for the genetic predisposition to enhanced nicotine reward to be expressed (13, 25, 26).

Method

Study Group

The participants were 615 9th grade high school students of

European ancestry, each of whom was enrolled in one of five public

high schools in northern Virginia. These adolescents were participating

in a longitudinal cohort study of biobehavioral determinants

of adolescent health habits. Of these 615 adolescents,

293 (48%) were male and 322 (52%) were female.

This study group is a subset of a larger cohort that was drawn

from 2,393 students identified through class rosters at the beginning

of 9th grade. Students were ineligible to participate in the cohort

study of adolescent health habits if they had a special classroom

placement (i.e., severe learning disability and/or English as

a second language). The cohort was formed in the 9th grade and

is being followed until the end of the 12th grade.

On the basis of the cohort selection criteria, a total of 2,120 students

(89%)