Noradrenergic gene variation shaping vulnerability and resilience by affecting mental health-related characteristics: A systematic review

Mental health problems are highly prevalent worldwide. Stress can precipitate both the onset and recurrence of mental health problems. While many individuals are exposed to similar stressors, there is a large heterogeneity in sensitivity to stress and the extent to which someone subsequently develops mental health issues. A key factor that contributes to an individual's capacity to cope with adversity, referred to as resilience, is genetic variation. Here, we systematically reviewed the effects of genetic variation in the genes encoding the norepinephrine (NE) transporter and receptors on resilience- and mental health-related features in a transdiagnostic approach (i.e., without restrictions regarding factors such as diagnosis or age). Our search yielded 49 studies for inclusion. The current evidence highlights that 1) genetic variations in the NE system (particularly in the ADRA2A and ADRA2B genes) exert influence on some cognitive processes, especially attention and emotional memory; 2) genetic variants in the alpha-2a receptor might play a role in some personality traits; 3) deletion in the ADRA2B and ADRA2C genes seems to be related with altered activity of the amygdala during emotional memory tasks; 4) the link between NE variants and response to methylphenidate are inconclusive. Altogether, these studies provide evidence for a genetic effect of the noradrenergic system in specific resilience- and mental health-related individual characteristics. However, the number of available studies specifically investigating noradrenergic genes were limited, emphasizing the need to perform more research on the noradrenergic system, while taking into account factors such as age, sex, environment, and the potential interactions with other genes.