Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis

Abstract

While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.

Fig. 1. Brain regions involved in processing social (cognitive) information.

An automatic meta-analysis using NeuroSynth identified a network ofregions involved in social processing. This network overlaps with the Default Mode Network, and includedthe dorsomedial and ventromedial prefrontal cortex, precuneus, temporal pole, and amygdala. Activity inthese regions during processing of faces was examined, and used as a predictor of psychotic experiences

Fig. 2. Final path model.

Associations between the observed variables are represented by straight arrow lines. The double-headed arrow represents covariance between the two polygenic risk scores. Information about all coefficients and co-variances can be found in the supplementary figure. **p < 0.01, *p < 0.05. ASD autism spectrum disorder, SCZ schizophrenia