Loneliness, Genetic Susceptibility, Brain Structure, and the Risk of Schizophrenia: A Large Prospective Study

Loneliness has been linked to adverse mental health outcomes, including psychosis, but its independent role in schizophrenia (SZ) development is unclear. We hypothesize that loneliness independently increases the risk of incident SZ and is associated with structural brain changes, especially in individuals with high genetic predisposition.

This prospective cohort study analyzed data from 491 613 UK Biobank participants aged 38-73 years without baseline SZ. Participants reported loneliness, provided demographic, socioeconomic, lifestyle information, and polygenic risk scores (PRSs) for SZ. Follow-up lasted until 2022, tracking incident SZ cases. Neuroimaging analyses examined gray matter volume associations with loneliness, considering genetic risk.

Over an average follow-up of 13.3 years, 675 individuals developed SZ. Those reporting loneliness (n = 91 017; 18.5%) had a significantly increased SZ risk, with an unadjusted hazard ratio (HR) of 3.84 (95% CI, 3.30-4.46). After adjusting for age, sex, socioeconomic factors, lifestyle, depression and anxiety symptoms, and PRS, the association remained stable (HR = 1.84; 95% CI, 1.36-2.49). Neuroimaging revealed widespread gray matter volume reductions linked to loneliness, notably in regions involved in emotion regulation and social cognition, such as the middle frontal gyrus, insula, hippocampus, and thalamus. These effects were more pronounced in individuals with higher SZ-PRS, with significant regional brain volume reductions among those with elevated genetic risk.

Loneliness independently predicts increased SZ risk and is associated with widespread brain volume changes, especially in genetically vulnerable individuals. Addressing loneliness may be a key strategy to mitigate SZ development and brain structural alterations.