Placental NEGR1 DNA methylation is associated with BMI and neurodevelopment in preschool-age children.

Studies have linked maternal pre-pregnancy obesity and hyperglycaemia with metabolic and neurodevelopmental complications in childhood. DNA methylation (DNAm) might enable foetal adaptations to environmental adversities through important gene loci. is involved in both energy balance and behaviour regulation. The aim of this study was to investigate associations between placental DNAm at the gene locus and childhood anthropometric and neurodevelopmental profiles in preschoolers. We analysed 276 mother-child dyads from Gen3G, a prospective birth cohort from Sherbrooke. At 3yo (40.4 ± 3.0 months), we measured body mass index (BMI) and the mothers reported on offspring neurobehavior using the Strengths and Difficulties Questionnaire (SDQ). We quantified DNAm levels at 30 CpGs at the locus using the MethylationEPIC Array in placental biopsies. DNAm at four CpGs located before second exon predicted child's BMI z-score (cg26153364: β=-0.16 ± 0.04; =0.008, cg23166710: β=0.14 ± 0.08; =0.03) and SDQ total score (cg04932878: β=0.22 ± 1.0; = 3.0x10, cg16525738: β=-0.14 ± 0.18; =0.01, cg23166710: β=-0.13 ± 0.36; = 0.04), explaining 4.2% (p=0.003) and 7.3% (= 1.3 x 10) of BMI-z and SDQ variances. cg23166710 was associated with both childhood phenotypes and correlated with placental expression (r=-0.22, =0.04), suggesting its possible functional role. Together, maternal metabolic characteristics during pregnancy with DNAm levels explained 7.4% (=4.2 x 10) of BMI-z and 14.2% (=2.8 x 10) of SDQ variance at 3yo. This longitudinal study suggests that placental DNAm is associated with adiposity and neurodevelopment in preschool children and highlights its potential role in their comorbidity.