Epigenetic signatures associated with the observed link between maternal tobacco use during pregnancy, and offspring conduct problems in childhood and adolescence

Maternal tobacco smoking during pregnancy is a large driver of health inequalities and a higher prevalence of conduct problem has been observed in exposed offspring. Further, maternal tobacco use during pregnancy can also alter offspring DNA methylation. However, currently, limited molecular evidence have been found to support this observation. Thus we aim to examine the association between maternal tobacco use in pregnancy and whether offspring Conduct problems is mediated by tobacco exposure-induced via DNA methylation differences. Understanding the etiology of the causal link will be crucial in the early identification and treatment of CP in children and adolescents. DNA was sourced from the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years in New Zealand. Bisulfite-based amplicon sequencing of 10 loci known to play a role in neurodevelopment, or with associations with CP phenotypes, was undertaken. We identified nominally significant differential DNA methylation at specific CpG sites in CYP1A1, ASH2L and MEF2C in individuals with Conduct problems who were exposed to tobacco in utero. We conclude that environmentally-induced DNA methylation differences could play a role in the observed link between maternal tobacco use during pregnancy and childhood/adolescent Conduct problems However, larger sample sizes are needed to produce an adequate amount of power to investigate this interaction further.### Competing Interest StatementThe authors have declared no competing interest.* CP : Conduct problems CHDS : Christchurch health and development study BSAS : Bisulfite based amplicon sequencing SIDS : Sudden infant death syndrome ADHD : Attention-deficit hyperactivity disorder DOHaD : Developmental origins of human health and disease GFI1 : Growth Factor Independent one transcriptional repressor CPS : Conduct disorder score AHRR : Aryl hydrocarbon receptor repressor ASH2L : ASH2 like histone lysine methyltransferase complex subunit BDNF : Brain-derived neurotrophic factor, CNTNAP2 : Contactin associated protein 2 CYP1A1 : Cytochrome P450 Family 1 Subfamily A Member 1 DUSP6 : Dual specificity phosphatase 6 GRIN2b : Glutamate Ionotropic Receptor NMDA Type Subunit 2B MEF2C : Myocyte enhancer factor 2C PRDM8 : PR/SET Domain 8 FC : Fold change CPM : Counts per million FDR : False discovery rate