Environmental adversity moderates polygenic score effects on childhood behavioral problems in the United States

IMPORTANCEBehavioral problems in children are influenced by environmental and genetic factors, but it is still unclear how much each contributes and if there are gene-by-environment interactions (GxE). OBJECTIVEOur object was to investigate how environmental adversity moderates the effects of polygenic scores (PGS) on childhood behavioral problems through additive and interaction effects. DESIGN, SETTING, AND PARTICIPANTSParticipants were N = 7, 191 children aged 7-15 years (50% autistic) from two United States cohorts, ABCD and SPARK. MAIN OUTCOMES AND MEASURESThe main outcomes were five dimensional subscales from the Child Behavior Checklist (CBCL). The genetic variables were 20 behavior-related PGS, including psychiatric diagnoses, substance use disorders, cognition, and personality PGS. Environmental adversity was estimated by the Area Deprivation Index (ADI). The ADI is a composite variable of neighborhood adversity based on education, income, and housing. RESULTSThirteen out of the 20 PGS were significantly associated with the ADI. PGS for psychiatric and substance use disorders were positively associated with the ADI, and PGS for educational attainment and cognitive performance were negatively associated. The ADI had significant SNP heritability: h2 = 0.33 [0.24, 0.42], with the estimate similar between ABCD and SPARK. The ADI was positively associated with more behavioral problems and explained more variance than any PGS, but this effect was reduced after accounting for these potential genetic confounders. Several GxE effects were identified, including: 1.) the positive associations of the cannabis and alcohol dependency PGS with externalizing problems increased as the ADI increased, 2.) the positive associations of the anorexia PGS with thought and internalizing problems increased as the ADI increased, 3.) the positive associations of the autism PGS with internalizing problems decreased as the ADI increased, 4.) the negative associations of the educational attainment and cognitive performance PGS with several behavioral problems increased as the ADI increased, and 5.) the extraversion PGS association with social problems was negative in an advantaged environment but positive in a disadvantaged environment. CONCLUSIONS AND RELEVANCEEnvironmental adversity estimated by the ADI moderates the effects of some PGS on childhood behavioral problems through additive and interaction effects. This highlights the importance of considering both genetic and environmental factors in understanding childhood behavioral problems. Our findings emphasize the need to include PGS of personality and cognitive traits, in addition to psychiatric PGS.