DNA Methylation Mediates the Association Between Prenatal Maternal Stress and the Broad Autism Phenotype in Human Adolescents: Project Ice Storm

Prenatal maternal stress (PNMS) predicts risk for autism spectrum disorders (ASD), although the mechanisms are unknown. Because ASD and autistic-like traits have been associated with both prenatal stress and DNA methylation differences, it is important to examine whether epigenetic mechanisms mediate the pathway from PNMS to later autistic-like outcomes. This study aimed to determine the extent to which DNA methylation mediates the association between PNMS from a natural disaster and autistic-like traits in offspring assessed during adolescence. Five months following the 1998 ice storm in Quebec, we recruited women who had been pregnant during the crisis and assessed their PNMS: objective hardship, subjective distress, and cognitive appraisal. At age 13, their children provided blood samples for DNA. At ages 15, 16 and 19, the youth self-reported their own autistic-like traits using the Broad Autism Phenotype Questionnaire. This longitudinal design allowed us to track the developmental pathway from prenatal exposure, through adolescent DNA methylation, to later behavioral outcomes. Analyses included youth with data on PNMS, DNA methylation, and the BAPQ (<i>n</i> = 27 at age 15; 22 at age 16; and 13 at age 19). Results showed that mothers' disaster-related objective hardship and their negative cognitive appraisal of the disaster were associated with DNA methylation at age 13, which then were associated with the severity of their children's Aloof Personality and Pragmatic Language Deficits, but not Rigid Personality, at ages 15, 16 and 19. Mediation was significant particularly through genes within the PI3K/AKT/mTOR pathway, which has been implicated in various neurodevelopmental disorders, including ASD. Interestingly, while greater PNMS predicted more severe ASD traits, the epigenetics effects were for less severe traits. Although other interpretations are possible, these results could suggest that DNA methylation, assessed in early adolescence, may protect against ASD traits at later ages, particularly when there is a mismatch between the prenatal environment (disaster) and the postnatal environment (absence of disaster). The interpretation of these findings benefits from the longitudinal design and is discussed in the context of fetal programming and the predictive adaptive response.