Subjective Well-being: A Key to Bridge Urbanization, Brain and Mental Health

The pursuit of happiness is a lifelong endeavor for everyone; nevertheless, elucidating its etiology, neurobiological substrates, and implications for mental health continues to pose significant challenges in contemporary research. This study sought to delineate the causal relationships among subjective well-being (SWB), urbanization, brain, and mental health, and to explore the protective role of SWB against prevalent psychiatric disorders. Utilizing data from 198,823 adults in the UK Biobank, including SWB questionnaires (five items), urban living environments (121 variables), neuroimaging data (2,413 measures), mental health assessments (39 indicators), and ICD-10 psychiatric diagnoses (10 disorders), we initially identified two robust SWB components using ten-fold cross-validated factor analysis: internal subjective well-being (ISWB) and social subjective well-being (SSWB). Phenome-wide association studies (PheWAS) revealed significant associations between urbanization variables and both ISWB (78/121) and SSWB (59/121); between neuroimaging indicators and both ISWB (416/2,413 measures) and SSWB (77/2,413); and between mental health assessments and both ISWB (38/39 indicators) and SSWB (37/39) (P < 0.05, Bonferroni corrected). Sequential mediation analysis uncovered 28 causal pathways from urbanization to brain to SWB to mental health (ISWB: 16 pathways, SSWB: 12 pathways), while the moderated mediation analysis revealed 19 pathways where SWB significantly moderated the urbanization → brain → mental health pathways (14 for ISWB, 5 for SSWB). Finally, Cox proportional hazards survival analysis demonstrated that individuals in the highest ISWB sextile had a 76% reduction in the overall risk of developing 10 mental disorders compared with those in the lowest sextile (Z = -29.49, Hazard Ratio [HR] = 0.24, P = 3.93e-191), and SSWB showed a 36% risk reduction (Z = -9.42, HR = 0.64, P = 4.50e-2). Moreover, both SWB components demonstrated the highest protective effects against depression (ISWB: HR = 0.13, SSWB: HR = 0.39). By systematically uncovering the causal pathways through which SWB components differentially participate in the regulation of urban living environments on the human brain, thereby affecting mental health, this study thus provides biological evidence and modifiable SWB indicators for the prevention of common psychiatric disorders.