The primary findings of this study are significant associations between the SLC6A4 5HTTLPR and categories of BMI, and between the MAOA promoter VNTR and categories of BMI among males. These associations were found controlling for other factors (gender, race/ethnicity, age, and parental education). A significant interaction effect was found for the association between these genes and BMI by both race/ethnicity and gender. The subsequent stratified analyses revealed that the association between SLC6A4 and excess BMI was significant for males overall, and for White and Hispanic males. SLC6A4 5HTTLPR genotypes were found to deviate from HWE in the cases (obese and overweight + obese) but not the controls (normal BMI), with the ss homozygote genotype found in excess of expectation. Stratified analyses for MAOA among males indicated that the promoter VNTR was significantly associated with overweight + obese in White and in Hispanic males, as well.
A unique contribution of this study is a previously unreported association between obesity and candidate gene SLC6A4 in a U.S. population-based sample. The findings of our study confirm findings from a recently published study demonstrating an association between the s
allele of the SLC6A4 5HTTLPR polymorphism and overweight among a sample of Argentinean children and adolescents (61
). They also extend these findings by providing evidence for association between overweight + obesity and the s
allele 5HTTLPR homozygote in males of Caucasian race and Hispanic ethnicity. The present findings regarding the association between SLC6A4 and BMI categories are consistent with the putative role of serotonin on food craving and obesity (28
) and the direction of the results are also consistent with the hypothesized expression effects of the 5HTTLPR polymorphism. The s
allele is believed to reduce the transcriptional activity of the promoter (63
) and is associated with less serotonin transporter protein (63
). An association between anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region has been noted (63
). Thus, one potential hypothesis for the association between this gene and obesity may be a mediating effect of increased dietary intake as a means of affect regulation.
Further, the findings of this study regarding an association between MAOA and BMI are interesting in light of one family-based study (41
) and two recent large-scale association studies (40
). Using the transmission disequilibrium test, evaluating the degree to which parents transmit this gene to their obese offspring, Camarena et al., (2004) found the low active variant to be associated with obesity (41
). Extending this in a large population-based study, Need et al., (2006) (40
) found that European Caucasian women (Mean age = 47 years) carriers of the low active variant were significantly more likely to be obese (BMI > 30). Ducci et al., (2006) found a significant association between BMI and MAOA genotype, with the low-activity allele associated with a higher BMI among a sample of primarily non-obese male participants with and without a history of alcohol dependence (65
Our findings indicated some interesting potential gender effects. Gene by gender interactions indicated the relationship between gene (specifically, SLC6A4 and MAOA) and overweight or overweight + obese were significant for males. Need et al. observed an association between MAOA and categories of BMI among their female sample, whereas no association between MAOA and categories of BMI was noted in our sample of females. This may reflect an age related effect, as the mean age of women in our study was much younger (mean age of 22 years in our study vs. mean age of 48 in Need et al. study). Expression of MAOA is affected by ovarian hormones which can fluctuate with age (66
). It has been shown that ovarian steroids, particularly estrogen, can decrease MAOA expression, resulting in elevated serotonin levels (66
). The degree to which these potential age-related effects represent a true effect will need to be verified in other samples with a wider age range.
Dopamine has been associated with the reinforcement value of food (68
) and variation in dopaminergic activity in the brain has been associated with obesity (13
). The association of the MAOA low activity VNTR variant and increased BMI from this study would be consistent, in part, with these observations since MAOA is implicated in dopamine metabolism (40
). However, we did not find that polymorphisms in the dopamine D2 and D4 receptors and the dopamine transporter were statistically significantly associated with BMI categories in this young adult sample. It is unlikely that these null results for the main effects models are a result of low statistical power, as many of the cell counts in these models for these dopamine related genes were of sufficient size and much larger than studies to date. Nevertheless, there are several possible explanations. First, candidate gene studies of the TaqI A polymorphism at the D2 dopamine receptor gene have not been completely consistent, with some studies reporting an association (15
) and other reporting no association (20
). Second, the difference in samples with regard to age and country of origin also make it difficult to compare our findings to other studies of dopamine candidate genes. Finally, there was only a single polymorphism within each candidate gene which was available for analysis. The authors only had access to the genotypes provided by the Add Health study, and could not perform further genotyping on the data set. It is possible that genetic variations in other parts of these (or other) genes in the dopaminergic system are associated with obesity in this population-based sample. However, it will require future studies to further examine this hypothesis.
The trends observed between DRD4 presented in our study are consistent with the findings reported by Guo et al. (24
) using this same public-use data set. These investigators employed a somewhat different analytic procedure using the complete sample of related and unrelated individuals and included data from the self-report of height and weight obtained by the Add Health study at Wave I. These investigators found a significant association between DRD4 and obesity among African-Americans and Hispanics. We chose to limit our analyses to unrelated individuals only, and we further limited our analysis by using measured height and weight assessed during young adulthood to construct BMI categories. When we examined the association between change in BMI and DRD4 we did find an association approaching significance (p = .07).
While we are enthusiastic about the findings presented here, caution is warranted in interpretation. Initial reports from candidate gene studies, in general, may overestimate the effect (71
) and modest yet significant effects are reported here. Also, we did not apply a Bonferroni correction because many of the phenotypic tests were related and this would have resulted in an over-conservative correction. However, a large number of statistical comparisons were conducted which may have potentially inflated the risk of Type I error. Thus, replication is needed before definitive conclusions can be made about the role of these genes on regulating weight and risk of obesity. Also, future studies are planned to examine the interactions with other psychological states and traits which may help to better explain these associations as some of the psychological states overlap with risk of obesity. Of note, we did not find that the associations that were present for Hispanics and American Whites were also present for African-Americans in this sample. Furthermore, the association observed for Whites between SLC6A4 and obesity did not exhibit the same pattern as it did for Hispanics. These differences may represent the reduced power in the stratified model, genetic heterogeneity within the Hispanic and African-American groups, or both factors. This will need to be further studied with larger sub-samples of non-Caucasian participants. Another limitation of the current study was that other indicators of adiposity or body composition (e.g., waist circumference, skin fold measures) were not present in the Add Health study. In general, BMI is a good proxy, but examining the association between these candidate genes and other indicators of adiposity and body composition would strengthen the findings. Also of note, these analyses did not account for age of pubertal onset which is potentially important to the analyses of change in BMI; however, given that the median age at Wave II was 17 (Mean = 16.5), this may have had little affect, as most participants would likely have been post-pubertal onset. Further, as described above, it would have been ideal to have additional candidate gene data available, and multiple polymorphisms within the genes in order to test other hypothesis as well as evaluate the effects of population stratification. However, currently only a limited amount of genetic data is available for analysis using this cohort.
Our findings lend further support to of the involvement of dopamine and serotonin regulation on energy balance (9
). The results underscore the need for additional research examining the role of these systems on BMI and other energy-balance behaviors (e.g., diet and physical activity). Additional work is needed to identify the potential complex gene by gene and gene by environment interactions that may further characterize these main effects.