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

ABSTRACT

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. NEGR1 is involved in both energy balance and behaviour regulation. The aim of this study was to investigate associations between placental DNAm at the NEGR1 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 NEGR1 locus using the MethylationEPIC Array in placental biopsies. DNAm at four CpGs located before NEGR1 second exon predicted child’s BMI z-score (cg26153364: β=−0.16 ± 0.04; p=0.008, cg23166710: β=0.14 ± 0.08; p=0.03) and SDQ total score (cg04932878: β=0.22 ± 1.0; p= 3.0x10⁻⁴, cg16525738: β=−0.14 ± 0.18; p=0.01, cg23166710: β=−0.13 ± 0.36; p= 0.04), explaining 4.2% (p=0.003) and 7.3% (p= 1.3 x 10⁻⁴) of BMI-z and SDQ variances. cg23166710 was associated with both childhood phenotypes and correlated with NEGR1 placental expression (r=−0.22, p=0.04), suggesting its possible functional role. Together, maternal metabolic characteristics during pregnancy with NEGR1 DNAm levels explained 7.4% (p=4.2 x 10⁻⁴) of BMI-z and 14.2% (p=2.8 x 10⁻⁷) of SDQ variance at 3yo. This longitudinal study suggests that placental NEGR1 DNAm is associated with adiposity and neurodevelopment in preschool children and highlights its potential role in their comorbidity.

KEYWORDS:

• Epigenetics
• DOHaD
• obesity
• foetal programming
• childhood development
• SDQ

Acknowledgments

The authors acknowledge all the participants from Gen3G and the staff of the Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS) who participated in the follow-up and data collection.

Authors’ contributions

EB wrote the manuscript, carried out the data analysis/interpretation under the supervision of LB. LB, MFH, and PP conceived the original study design. RVL proposed the use of the SDQ Questionnaire and supported SDQ-related data analysis and interpretation. VGO participated in the gene expression analyses and the data analyses. All authors revised the manuscript and approved its final version.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

EB is recipient of a financial support from the Faculté de médecine et des sciences de la santé (FMMS) from the Université de Sherbrooke. VGO is supported by a doctoral training award from the Fonds de recherche du Québec - Santé (FRQS). LB is a senior research scholar from the FRQS. MFH is a recipient of an American Diabetes Association Pathways Accelerator Award (#1-15-ACE-26). RV is the Canada Research Chair in the Perinatal Programming of Mental Disorders. LB, MFH and PP are members of the FRSQ-funded CRCHUS. This project has been funded by the Canadian Institutes of Health Research (Grant # PJT-152989).