Prenatal Cannabis Exposure, Genetic Predispositions, and Autism Spectrum Disorder Traits in the Adolescent Brain Cognitive Development Study

Background: Prenatal cannabis exposure (PCE) may be associated with increased risk of Autism Spectrum Dis-order (ASD). However, the degree that this increased risk is influenced by genetic or familial confounders is not well understood. This study evaluated whether (1) polygenic risk would predict ASD traits; (2) PCE would pre-dict ASD traits above and beyond ASD genetic risk; and (3) the association between PCE and ASD traits would be weakened once familial confounders were also controlled. Method: This was a retrospective, population-based study using data from the Adolescent Brain Cognitive De-velopment (ABCD) study 4.0 release. Children born between 2005- 2009 with genotypic data were included with-in the analyses. At baseline, children were between 9 and 11 years of age (M=9.92, SD=0.52) and follow-up was one year later. Mothers retrospectively reported cannabis use during pregnancy. A polygenic score (PGS) for ASD was developed using PRS-CS based on summary statistics from a genome wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls. ASD traits were measured using caregiver reports on the Short Social Responsiveness Scale (SRS). Hypotheses were tested using regression models that accounted for PGS and familial confounders (propensity score). Results: PGS was associated with total SRS (β =0.09, 95% Confidence Interval [0.05, 0.13]) and all individual items on the SRS, except Focus. PCE accounted for significant variance in all measured ASD traits and total SRS above genetic risk. In models controlling for both PGS and propensity scores, PCE remained positively associated with several ASD traits and the SRS total score, but not with social communication aspects of ASD. Conclusions: PCE remained positively associated with total SRS and several ASD traits, even after accounting for individual genetic risk and family confounders. Potential specificity of PCE effects on subtypes of ASD traits warrants further attention. Keywords: prenatal cannabis exposure, polygenic risk, autismAbbreviations: PCE = prenatal cannabis exposure, ABCD = Adolescent Brain Cognitive Development, ASD = autism spectrum disorder, PGS = polygenic score, Short Social Responsiveness Scale = SRS