Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD

Kristina Gervin, Hedvig Nordeng, Eivind Ystrom, Ted Reichborn-Kjennerud, Robert Lyle

Epidemiological studies have shown that long-term exposure to paracetamol during pregnancy is associated with attention-deficit/hyperactivity disorder (ADHD). The mechanism by which paracetamol may modulate the increased risk of developing ADHD is currently unknown. We have conducted an epigenome-wide association study (n = 384 cord blood samples) and investigated whether prenatal exposure to paracetamol is associated with DNA methylation in children diagnosed with ADHD. Analyses identified significant differences in DNA methylation (n = 6211 CpGs) associated with prenatal exposure to paracetamol for more than 20 days in children diagnosed with ADHD compared to controls. In addition, these samples were differentially methylated compared to samples with ADHD exposed to paracetamol for less than 20 days (n = 2089 CpGs) and not exposed to paracetamol (n = 193 CpGs). Interestingly, several of the top genes ranked according to significance and effect size have been linked to ADHD, neural development, and neurotransmission. Gene ontology analysis revealed enrichment of pathways involved in oxidative stress, neurological processes, and the olfactory sensory system, which have previously been implicated in the etiology of ADHD. These initial findings suggest that in individuals susceptible to ADHD, prenatal long-term exposure to paracetamol is associated with DNA methylation differences compared to controls.