Maternal Smoking During Pregnancy Is Associated With DNA Methylation in Early Adolescence: A Sibling Comparison Design

Maternal smoking during pregnancy (MSDP) may impact offspring biological (e.g., deoxyribonucleic acid methylation [DNAm]) and behavioral (e.g., attention-deficit/hyperactivity disorder hyperactive/impulsive [ADHD-HI] symptoms) development. There has been consistency in findings of differential methylation in global DNAm, and the specific genes AHRR, CYP1A1, CNTNAP2, MYO1G, and GFI1 in relation to MSDP. The current study aims to (a) replicate the associations of MSDP and DNAm in prior literature in middle childhood–adolescence (cross-sectionally) using a sibling-comparison design where siblings were discordant for MSDP (n= 328 families; M_age Sibling 1= 13.02; Sibling 2= 10.20), adjusting for prenatal and postnatal covariates in order to isolate the MSDP exposure on DNAm. We also (b) cross-sectionally explored the role of DNAm in the most robust MSDP–ADHD associations (i.e., with ADHD-HI) previously found in this sample. We quantified smoking exposure severity for each sibling reflecting time and quantity of MSDP, centered relative to the sibling pair’s average (i.e., within-family centered, indicating child-specific effects attributable MSDP exposure) and controlling for the sibling average MSDP (i.e., between-family component, indicating familial confounding related to MSDP). We found that child-specific MSDP was associated with global DNAm, and CNTNAP2, CYP1A1, and MYO1G methylation after covariate adjustment, corroborating emerging evidence for a potentially causal pathway betweenMSDPandDNAm. Therewas some evidence that child-specific CNTNAP2 and MYO1G methylation partially explained associations between MSDP and ADHD-HI symptoms, though only on one measure (of two). Future studies focused on replication of these findings in a longitudinal genetic design could further solidify the associations found in the current study.