Exploring the behavioral and emotional manifestation of polygenic risk for psychiatric disorders among school children

The largest genome-wide association studies (GWAS) of psychiatric disorders are based on comparisons between diagnosed cases versus controls. The extent to which results derived from case/control comparisons capture the genetic underpinnings of behavioral and emotional problems during childhood and adolescence among general population remains to be established. The current study examined associations between polygenic risk scores (PRS) for psychiatric disorders and a wide-range of behavioral and emotional problems among schoolchildren. The study included a total of 4,712 individuals from the INSchool cohort (mean age=10.0 years; SD=3.0, range=5-18, 45% females) with behavioral and genetic data available. PRS were calculated using summary statistics from the most recent and largest GWAS of attention-deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder depression, schizophrenia and anxiety using the PRScs software. Behavioral and emotional problems were assessed using the Child Behavior Checklist (CBCL), the Teacher's Report Form (TRF), the Youth Self-Report (YSR) and the Strengths and Difficulties Questionnaire (SDQ) reported by parents, teachers and participants over 11 years. Associations between PRS and behavioral and emotional problems were examined using linear mixed-effects models with age, sex, socio-economic status and 20 principal genetic components as covariates and school as random effects to account for the multilevel nature of the data (i.e. children within schools). PRS for ADHD, ASD, depression and anxiety showed significant associations with behavioral and emotional problems in the expected direction after multiple testing correction. PRS for ADHD showed the strongest associations with a wide range of behavioral and emotional problems reported by all the three informants. Stratified results by sex showed that polygenic risk for ADHD was associated with self-reported psychopathology only among girls. Furthermore, associations with polygenic risk for schizophrenia, depression and autism were observed only among boys. However, only the associations between PRS for schizophrenia and parent-reported scores on internalizing, anxiety and depression and total problems from the CBCL were significantly stronger among boys compared to girls (P-interaction < 0.05). Next analyses will examine mutually adjusted models including PRS for ADHD, ASD, depression and anxiety and explore whether they are related to differential profiles of behavioral and emotional problems scores. Common genetic risk variants for childhood-onset neurodevelopmental disorders such as ADHD may be underlying the early manifestation of psychopathology expressed through behavioral and emotional problems in the general population. The fact that PRS for ADHD showed a more ubiquitous psychopathological expression compared to ASD which is also an early-onset neurodevelopmental disorder may be related to the difference in power of the original GWAS used to construct the PRS. Interestingly, depression was mainly associated with self and parent reported outcomes which may be explained by the different contexts in which parents and teachers interact with young individuals. Overall, our findings suggest that polygenic risk for ADHD and, to less extent, ASD and depression may be underlying the early manifestation of psychopathology among the general population.