Reviewer #2 (Public Review): Gene-Environment Pathways to Cognitive Development and Psychotic-Like Experiences in Children

Abstract

In children, psychotic-like experiences (PLEs) are related to risk of psychosis, schizophrenia, and other mental disorders. Maladaptive cognitive functioning is a well-known risk factor and early marker for psychosis, schizophrenia, and other mental disorders. Since cognitive functioning is linked to various genetic and environmental factors during development, we hypothesize that it mediates the effects of those factors on childhood PLEs. Using large, representative, longitudinal data, we tested the relationships of genetic and environmental factors (such as familial and neighborhood environment) with cognitive intelligence and their relationships with current and future PLEs in children.To estimate unbiased associations against potential confounding variables, we leveraged large-scale, representative, multimodal data of 6,602 children (aged 9-10 years old; 47.15% females; 5,211 European-ancestry) from the Adolescent Brain and Cognitive Development Study. Linear mixed model and a novel structural equation modeling (SEM) method that allows unbiased estimation of both components and factors were used to estimate the joint effects of cognitive capacity polygenic scores (PGSs), familial and neighborhood socioeconomic status (SES), and supportive environment on NIH Toolbox cognitive intelligence and PLEs. We adjusted for ethnicity (genetically defined), schizophrenia PGS, and additionally unobserved confounders (using computational confound modeling).We identified that lower cognitive intelligence and higher PLEs correlated significantly with several genetic and environmental variables: i.e., lower PGSs for cognitive capacity, lower familial SES, lower neighborhood SES, lower supportive parenting behavior, and lower positive school environment. In SEM, lower cognitive intelligence significantly mediated the genetic and environmental influences on higher PLEs (Indirect effects of PGS: β range=-0.0355∼ -0.0274; Family SES: β range=-0.0429∼ -0.0331; Neighborhood SES: β range=0.0126∼ 0.0164; Positive Environment: β range=-0.0039∼ -0.003). Supportive parenting and a positive school environment had the largest total impact on PLEs (β range=-0.152∼ -0.1316) than genetic or environmental factors.Our results reveal the role of genetic and environmental factors on children’s risk for psychosis via its negative impact on cognitive intelligence. Our findings have policy implications in that improving the school and family environment and promoting local economic development might be a way to enhance cognitive and mental health in children.