We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.

SummaryBackgroundThe associations of social isolation and loneliness with premature mortality are well known, but the risk factors linking them remain unclear. We sought to identify risk factors that might explain the increased mortality in socially isolated and lonely individuals.MethodsWe used prospective follow-up data from the UK Biobank cohort study to assess self-reported isolation (a three-item scale) and loneliness (two questions). The main outcomes were all-cause and cause-specific mortality. We calculated the percentage of excess risk mediated by risk factors to assess the extent to which the associations of social isolation and loneliness with mortality were attributable to differences between isolated and lonely individuals and others in biological (body-mass index, systolic and diastolic blood pressure, and handgrip strength), behavioural (smoking, alcohol consumption, and physical activity), socioeconomic (education, neighbourhood deprivation, and household income), and psychological (depressive symptoms and cognitive capacity) risk factors.Findings466 901 men and women (mean age at baseline 56·5 years [SD 8·1]) were included in the analyses, with a mean follow-up of 6·5 years (SD 0·8). The hazard ratio for all-cause mortality for social isolation compared with no social isolation was 1·73 (95% CI 1·65–1·82) after adjustment for age, sex, ethnic origin, and chronic disease (ie, minimally adjusted), and was 1·26 (95% CI 1·20–1·33) after further adjustment for socioeconomic factors, health-related behaviours, depressive symptoms, biological factors, cognitive performance, and self-rated health (ie, fully adjusted). The minimally adjusted hazard ratio for mortality risk related to loneliness was 1·38 (95% CI 1·30–1·47), which reduced to 0·99 (95% CI 0·93–1·06) after full adjustment for baseline risks.InterpretationIsolated and lonely people are at increased risk of death. Health policies addressing risk factors such as adverse socioeconomic conditions, unhealthy lifestyle, and lower mental wellbeing might reduce excess mortality among the isolated and the lonely.FundingAcademy of Finland, NordForsk, and the UK Medical Research Council.

Background Personality is suggested to be a major risk factor for depression but large-scale individual-participant meta-analyses on this topic are lacking. Method Data from 10 prospective community cohort studies with a total of 117 899 participants (mean age 49.0 years; 54.7% women) were pooled for individual-participant meta-analysis to determine the association between personality traits of the Five Factor Model and risk of depressive symptoms. Results In cross-sectional analysis, low extraversion (pooled standardized regression coefficient (B)=-0.08; 95 % confidence interval=-0.11, -0.04), high neuroticism (B=0.39; 0.32, 0.45), and low conscientiousness (B=-0.09; -0.10, -0.06) were associated with depressive symptoms. Similar associations were observed in longitudinal analyses adjusted for baseline depressive symptoms (n=56,735; mean follow-up of 5.0 years): low extraversion (B=-0.03; -0.05, -0.01), high neuroticism (B=0.12; 0.10, 0.13), and low conscientiousness (B=-0.04; -0.06, -0.02) were associated with an increased risk of depressive symptoms at follow-up. In turn, depressive symptoms were associated with personality change in extraversion (B=-0.07; 95 % CI=-0.12, -0.02), neuroticism (B=0.23; 0.09, 0.36), agreeableness (B=-0.09; -0.15, -0.04), conscientiousness (B=-0.14; -0.21, -0.07), and openness to experience (B=-0.04; -0.08, 0.00). Conclusions Personality traits are prospectively associated with the development of depressive symptoms. Depressive symptoms, in turn, are associated with changes in personality that may be temporary or persistent.