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

IMPORTANCE Behavioral 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). OBJECTIVE Our 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 PARTICIPANTS Participants were N = 7, 191 children aged 7-15 years (50% autistic) from two United States cohorts, ABCD and SPARK. MAIN OUTCOMES AND MEASURES The 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. RESULTS Thirteen 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: h 2 = 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 RELEVANCE Environmental 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Institutes of Health (DC014489 to JJM),as well as grants from the Simons Foundation (SFARI 516716 to JJM), the Clinical and Translational Science Award (KL2TR001877 to JJM), and the National Institutes of Health Predoctoral training grant (T32GM008629 to TRT). The Roy J. Carver Charitable Trust supports the work of JJM. Additionally, this work was supported by the University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center (Hawk-IDDRC) through the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103556). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ABCD data is publicly available, as is most of the SPARK data. However, a subset of the SPARK data is from a Research Match study that was approved by the University of Iowa IRB (IRB 202002251). This Research Match study has been published and is cited in this submission. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The SPARK genetic data can be obtained at SFARI Base: . Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (), held in the NIMH Data Archive (NDA).