Alcohol dependence withdrawal can be regarded as an acute stressor, and NPY is conducive to coping with stress-related psychological disorders. Thus, the purpose of this study was to explore the interaction between alcohol dependence and NPY rs16147 and its role in the occurrence of depression during the period of ADW. The results revealed that during the period of ADW, when the degree of alcohol dependence was low, NPY rs16147 CC homozygotes showed a lower degree of depression compared with those who carried the NPY rs16147 T allele. When the degree of alcohol dependence was high, the result was reversed. Further, the model conformed to the differential susceptibility model.
We firstly identified the role of the NPY rs16147 × alcohol dependence interaction in depression and then competitive model-testing analysis was employed to evaluate which gene and disease interaction model was the best fit for the data. The results revealed that the weak differential susceptibility model was the best fit. This indicates that CC homozygotes react differently to depression in the adverse or positive condition of alcohol dependence during the period of ADW. Individual genetic variation and the interactions between genes and external factors may characterize neural circuits and neurochemical functions, which represent the psychological strength of adaptable individuals. Stress-related events (such as ADW) can increase an individual’s susceptibility to serious psychiatric problems such as depression. Considering that genetic factors contribute to recovery, it is necessary to identify candidate genetic variations to explain genetic patterns.
Alcohol dependence withdrawal can give rise to increased CRF synthesis and release[24]. CRF is a stress-promoting neuropeptide which is dysregulated by long-term high-dose alcohol exposure. It can induce anxiogenic behaviors or other stress-related symptoms[18]. Interestingly, NPY and CRF show high neuroanatomical overlap but opposite function[25]. The current researches have consistently pointed out that NPY mainly counteracts alcoholism anxiety and stress-related symptoms caused by CRF in alcohol dependence[18], which suggests the effect of NPY on emotional homeostasis.
The expression of NPY is related to the polymorphism of the NPY gene as well as change in NPY expression. Single nucleotide polymorphisms (SNPs) are genetic variations of nucleotides that may be of functional significance. For the NPY gene, one of the main genetic variations is rs16147, which is located in the promoter region upstream of the NPY gene[26]. The results of this study suggest that rs16147 may play a role in the regulation of emotions, especially in terms of an interaction with alcohol dependence. In relation to the underlying internal mechanisms, there are still some unknowns. Even though, existing researches show that CC homozygotes is associated with stress-related psychopathology[27]; thus, the current findings may be explained by the fact that individuals with genetic variation respond differently to different degrees of alcohol dependence. Zhou et al. found that healthy individuals with low NPY expression genotypes and CC homozygotes had increased amygdala activity during the stress response [28]. Depression is associated with an increased response to negative stimuli in the amygdala. When the degree of alcohol dependence is increased, the amygdala activity in CC homozygotes may be enhanced. This may explain why CC homozygotes are more likely to be depressed in an adverse environment. Additionally, the current results indicated that individuals with the T allele exhibited about the same amount of depression in the case of severe alcohol dependence and in the condition of mild alcohol dependence. This finding aroused our interest. It has been reported that NPY rs16147 can interact with chronic stress and affect autonomic control, of which the T genotype is associated with vagal activity. Under high chronic stress, vagus nerve activity was found to be increased in patients with the T genotype[29]. Thus, it may be that with an increased degree of alcohol dependence, T allele carriers can increase their capacity to cope with depression by regulating the levels of vagal activity.
These findings shed light on the potential mechanism of NPY rs16147 in depression during ADW. According to the mechanism of genetic susceptibility, individuals of different genotypes showed different characteristics under stress. The early adverse environment may change the concentration of NPY, which can further induce stress-related psychopathology for some genotypes. Moreover, for some individuals, genetic resilience may enable the generation of more psychological resources in the face of adverse environmental stressors. In the current study, T allele carriers were able to adjust their state of emotion when dealing with adverse alcohol dependence, while CC homozygotes may have trouble dealing with a bad mood when experiencing severe alcohol dependence.
These findings provide some guidance for the prevention of depression during alcohol withdrawal for individuals with alcohol dependence. Firstly, in the case of high-risk individuals (CC homozygotes), we can intervene in advance so as to prevent exacerbation of depression; for individuals with the T allele, we can enhance their ability to adjust themselves when facing adverse environments. A systematic review of the factors associated with relapse of alcohol use indicated that emotion change can lead to alcohol dependence relapse[30]. Therefore, in the long run, the probability of recurrence of alcohol dependence can be reduced by improving depressive symptoms during ADW.
Several limitations of this study should be addressed. First, this study focused on male Chinese individuals, which may not be generalizable to the Chinese population. Second, as a cross-sectional study, the emotion and alcohol dependence status of the participants were only measured once; thus, the long-term association between depression and alcohol dependence among participants with different genotypes could not be detected. Third, the data were collected using self-rating scales, so there may be reporting bias.
In conclusion, there was an interaction between NPY rs16147 and alcohol dependence indicating that rs16147 might correlate with susceptibility for depressive symptoms among male adults with alcohol dependence during the period of ADW. These findings provide support for the differential susceptibility model, in which the CC homozygote of rs16147 was a plasticity factor rather than a factor that only increased the depression symptoms of individuals during ADW. These empirical findings have important implications for understanding the genetic moderation of alcohol dependence and its effect on individual differences in depression symptoms during the period of ADW. Further work is required to explore the underlying mechanisms of depression modulation at the molecular level, especially in relation to functional studies of neural systems.