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

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).

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.

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.

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