DNA Methylation of Neurodevelopmental, Stress-Response, Reward, and Opioid Pathway Genes: Sex Differences in Infants with Neonatal Opioid Exposure

Objective: To investigate sex-specific associations between DNA methylation (DNAm) of neurodevelopmental, stress-response, and dopaminergic pathway genes and need for pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS) among opioid-exposed newborns. Study Design: Buccal swabs were collected at birth from 181 infants in the multi-site Child and Family Study (CAFS). DNAm was measured via pyrosequencing at CpG sites within promoter regions of neurodevelopmental (BDNF), stress-response (AVP, NR3C1, OXTR, FKBP5, SLC6A4), dopaminergic (DRD2, DRD4), and opioid signaling (OPRM1) genes. Need for pharmacological treatment for NOWS was obtained from medical records. We estimated robust linear regression models to investigate sex-specific associations of DNAm and need for NOWS treatment. Estimated marginal means quantified sex-specific DNAm differences by treatment status. Results: After correction for multiple testing, five CpG sites within DRD4 were significantly associated with need for pharmacological treatment, with four sites showing higher DNAm in treated infants and one showing lower DNAm. Significant sex-specific associations were identified within DRD4 and AVP. Conclusions: Epigenetic variation across multiple biological pathways contributes to variability in NOWS severity among infants with prenatal opioid exposure. The relationship between epigenetic variation and need for NOWS treatment may vary depending on infant sex.