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.
The amygdala is one of the most widely connected structures in the primate brain and plays a key role in social and emotional behavior. Here, we present the first genome- wide association study (GWAS) of whole-brain resting-state amygdala networks to discern whether connectivity in these networks could serve as an endophenotype for social behavior. Leveraging published resting-state amygdala networks as a priori endophenotypes in a GWAS meta-analysis of two adolescent cohorts, we identified a common polymorphism on chr.8p23.2 (rs10105357 A/G, MAF (G)=0.35) associated with stronger connectivity in the medial amygdala network (beta=0.20, p=2.97x10-8). This network contains regions that support reward processes and affiliative behavior. People carrying two copies of the minor allele for rs10105357 participate in more prosocial behaviors (t=2.644, p=0.008) and have higher CSMD1 expression in the temporal cortex (t=3.281, p=0.002) than people with one or no copy of the allele. In post-mortem brains across the lifespan, we found that CSMD1 expression is relatively high in the amygdala (2.79 fold higher than white matter, p=1.80x10-29), particularly so for nuclei in the medial amygdala, reaching a maximum in later stages of development. Amygdala network endophenotyping has the potential to accelerate genetic discovery in disorders of social function, such as autism, in which CSMD1 may serve as a diagnostic and therapeutic target.
Adolescence is marked by changes in cognitive abilities and in several MRI-based measures of brain structure. This study took an individual-differences approach to help understand adolescent cognitive development in a large-sample longitudinal cohort, the IMAGEN study (initial n = 2,316). We used a latent change score model to assess the associations between levels and changes in the brain’s grey-matter regions and latent general cognitive ability between ages 14 and 19 years. As expected, higher cognitive ability was correlated with higher cortical volume and larger surface area, with more ambiguous results for cortical thickness. Higher-ability participants at age 14 tended to have accelerated subsequent cortical thinning, as well as cortical volume loss. There was no statistically significant link between changes in cognitive ability and changes in the brain measures we used. We also attempted to predict levels and changes in the brain and in cognitive ability using a polygenic score for genetic variants linked to educational attainment: the score was modestly associated with the baseline measures, but did not predict the trajectory of change in any measure to a statistically significant degree. Age-14 cortical volume and surface area—though not cortical thickness—mediated a portion (9-10%) of the association between the polygenic score and age-19 cognitive ability. These findings demonstrate how large-sample data can shed light on the links between brain and cognitive ability in this important phase of the lifespan.
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