Polygenic risk score, healthy lifestyles, and risk of incident depression.

Genetic factors increase the risk of depression, but the extent to which this can be offset by modifiable lifestyle factors is unknown. We investigated whether a combination of healthy lifestyles is associated with lower risk of depression regardless of genetic risk. Data were obtained from the UK Biobank and consisted of 339,767 participants (37-73 years old) without depression between 2006 and 2010. Genetic risk was categorized as low, intermediate, or high according to polygenic risk score for depression. A combination of healthy lifestyles factors-including no current smoking, regular physical activity, a healthy diet, moderate alcohol intake and a body mass index <30 kg/m2-was categorized into favorable, intermediate, and unfavorable lifestyles. The risk of depression was 22% higher among those at high genetic risk compared with those at low genetic risk (HR = 1.22, 95% CI: 1.14-1.30). Participants with high genetic risk and unfavorable lifestyle had a more than two-fold risk of incident depression compared with low genetic risk and favorable lifestyle (HR = 2.18, 95% CI: 1.84-2.58). There was no significant interaction between genetic risk and lifestyle factors (P for interaction = 0.69). Among participants at high genetic risk, a favorable lifestyle was associated with nearly 50% lower relative risk of depression than an unfavorable lifestyle (HR = 0.51, 95% CI: 0.43-0.60). We concluded that genetic and lifestyle factors were independently associated with risk of incident depression. Adherence to healthy lifestyles may lower the risk of depression regardless of genetic risk.