Maternal Smoking during Pregnancy and Autism: Applying Genetic and Epigenetic Approaches in a Birth Cohort Study.

Background: An association between maternal smoking in pregnancy and autism may be biologically plausible, but the evidence to date is inconsistent. In particular, it is difficult to rule out the possibility of unobserved or residual confounding when investigating causal effects in observational studies. One way to address this is by using genetic variants as proxies of exposure in a Mendelian randomization framework. Furthermore, the possibility of measurement error in self reports of smoking is difficult to address. Since smoking during pregnancy is robustly associated with changes in DNA methylation, using this information by means of an ‘epigenetic score’ for smoking may be more reliable than self-reported smoking.

Objectives: We aimed to investigate the causal relationship between maternal smoking during pregnancy (measured by self-report and by a DNA-methylation score) and offspring autism and autistic traits using conventional analysis, Mendelian randomization and paternal smoking as a negative control.

Methods: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large birth cohort study in the Bristol and surrounding areas of the UK. We investigated the effect of maternal smoking during pregnancy (exposure) on autism diagnosis and high scores on four autistic traits (outcomes) including the Social and Communication Disorders Checklist (SCDC) score, the Childhood Communication Checklist (CCC) coherence score, a score for repetitive behavior, and sociability subscale of the Emotionality Activity and Sociability temperament score. Maternal prenatal smoking was self-reported and also identified by computing a well-characterized DNA methylation score for adult smoking in the mothers when they were pregnant. Partners’ smoking during pregnancy was used as a negative control for intrauterine exposure. Mendelian randomization was carried out using the genetic variation at the CHRNA3locus in maternal DNA, as a proxy for heaviness of smoking.

Results: In conventional analysis, there was an association between smoking during pregnancy and impairments in social cognition [OR=1.52, 95% CI=1.20,1.92] and repetitive behaviors after adjusting for sex, maternal age, parity, maternal education, social class and financial difficulties. There was no evidence of such associations for the other traits or a diagnosis of autism. Paternal smoking was also associated with similar odds as for mothers, of impairments in social cognition [OR=1.44, 95% CI=1.15,1.81] and repetitive behaviors suggesting shared confounding. There was no evidence of an association of smoking exposure measured through DNA methylation on the autism traits. Genetic variation at CHRNA3 for heaviness of smoking was not associated with ASD or any of the autistic traits.

Conclusions: Our results do not support a causal association between maternal smoking during pregnancy and offspring autism or autistic traits. Previous studies finding such an association may have been prone to residual confounding.