Prolonged Childhood and Adolescent Loneliness in First-Episode Psychosis: Synergistic Polygenic Effects and Functional Outcomes

BACKGROUND: Prolonged childhood and adolescent loneliness (CAL) may mark an early socio-emotional vulnerability relevant to psychosis and interact with genetic liability. We examined whether CAL increases odds of first-episode psychosis (FEP), relates to diagnostic subtype and functioning, and interacts with polygenic risk scores (PGS) for schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MDD).

STUDY METHODS: We analyzed 2565 participants (1084 FEP, 1481 controls) from European Gene-Environment Interactions in Schizophrenia (EU-GEI) study. CAL was assessed retrospectively before age 12 (LNL12) and at 12-16 years (LNL12-16). Functioning was rated with a modified Global Assessment of Functioning (GAF). Genome-wide PGS for SCZ, BIP, and MDD were calculated using polygenic risk score-continuous shrinkage. Mixed-effects logistic and linear regression models tested associations of CAL with FEP, subtype, and functioning, including sex-stratified analyses. Additive gene-environment interaction was examined using dichotomized PGS and the Relative Excess Risk due to Interaction.

STUDY RESULTS: Both LNL12 (OR = 2.90, 95% CI, 2.30-3.66) and LNL12-16 (OR = 2.34, 95% CI, 1.94-2.84) were associated with FEP, independent of premorbid social isolation. CAL increased FEP odds in both sexes. LNL12-16, but not LNL12, was associated with affective versus non-affective psychosis (OR = 1.37, 95% CI, 1.02-1.83), more clearly in females (OR = 1.79, 95% CI, 1.16-2.77). CAL was also associated with poorer functioning, with 3-4-point lower GAF Disability scores. Significant additive interactions were observed between LNL12-16 and SCZ-PGS, and between LNL12 and MDD-PGS, although the latter did not replicate in European-ancestry sensitivity analyses.

CONCLUSIONS: Prolonged CAL is linked to higher risk of FEP, preferentially affective psychosis in females, poorer functioning, and developmental potentiation of polygenic liability.