Maternal Factors Modifying the Link Between Genetic Risk for Autism and Developmental Milestones

Although common genetic liability-quantified through polygenic risk scores (PRS)-accounts for substantial variance in autism spectrum disorder (ASD) liability, how prenatal environmental exposures interact with genetic predisposition to shape developmental outcomes remains poorly understood. Using the data from Autism Genetic Resource Exchange (AGRE), we examined whether maternal prenatal factors moderate the association between ASD PRS and developmental outcomes, including language delay, motor delay, and core ASD traits. In exploratory gene-environment interaction analyses, amniocentesis was a candidate positive moderator of the association between PRS and both language and motor delay, such that higher polygenic liability was associated with a greater likelihood of these delays among prenatally exposed children. First-trimester vaginal bleeding showed a similar positive interaction estimate for motor delay. Maternal use of over-the-counter (OTC) medications during pregnancy-predominantly acetaminophen, reported by 59.9% of OTC users-was associated with an inverse interaction estimate, corresponding to a decreased association between polygenic liability and language delay among exposed children. These observations suggest that several prenatal factors may modify the association between common genetic liability and developmental outcomes among autistic children and should be considered hypothesis-generating until replicated in larger, population-based cohorts. Replication in independent samples, together with analyses that address selection and confounding, will be required before these candidate gene-environment interactions can be interpreted as reflecting specific developmental mechanisms.