Genetic Risk, Incident Depression, and the Benefits of Adhering to a Healthy Lifestyle: A Prospective Analysis of the UK Biobank Cohort

Abstract

Background: Genetic factors increase the risk of depression, but the extent to which this can be offset by lifestyle factors is unknown. In the present study, we investigated whether a healthy lifestyle is associated with lower risk of depression regardless of genetic risk. Methods: Data for this prospective analysis were obtained from the UK Biobank and consisted of 339,944 participants (37-73 years old) without depression between 2006 and 2010. Genetic risk was categorized as low (quintile 1), intermediate (quintiles 2-4), or high (quintile 5) according to polygenic risk scores for depression. Healthy lifestyle scores — including no current smoking, regular physical activity, a healthy diet, and a body mass index < 30 kg/m2 — was categorized into favorable, intermediate, and unfavorable lifestyles. Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs) of the associations of genetic risk and lifestyle factors with depression. Finding: During a median follow-up of 8.1 years (2,723,692 person-years), 5,749 incidences of depression were ascertained. The risk of depression was 25% higher among those at high genetic risk compared with those at low genetic risk (HR = 1.25, 95% CI: 1.15-1.36). Unfavorable lifestyle was associated with a 70% increased risk of depression compared with that of a favorable lifestyle (HR = 1.70, 95% CI: 1.57-1.84). Of the participants with a high genetic risk and unfavorable lifestyle, 2.75% (95% CI, 2.36%-3.19%) developed depression compared with 1.25% (95% CI: 1.15%-1.36%) of participants with low genetic risk and a favorable lifestyle (HR = 2.06, 95% CI: 1.74-2.45). There was no significant interaction between genetic risk and healthy lifestyle (P for interaction = 0.75). Among participants at high genetic risk, a favorable lifestyle was associated with a 40% lower relative risk of depression than an unfavorable lifestyle (HR = 0.60, 95% CI: 0.51-0.72). Interpretation: Genetic and combined lifestyle factors were independently associated with the incidence of depression. Hence, our findings suggest that a healthy lifestyle may lower the risk of depression across different genetic risk categories, emphasizing the benefit of adherence to a healthy lifestyle independent of genetic risk. Funding Statement: National Natural Science Foundation of China (91746205, 71910107004, 71673199). Declaration of Interests: The authors declare that they have no conflicts of interests. Ethics Approval Statement: Not required.