Associations between in utero environment, DNA methylation and brain development: longitudinal investigations in monozygotic twins

• In Event: 2-122 - From child conception to adulthood: why epigenetic data analysis should be integrated into longitudinal studies

Integrative Statement

Introduction: Studies have shown that the quality of the in utero environment, which can be indexed by birth weight (BW), is predictive of brain development in adolescence and adulthood. Work in monozygotic (MZ) twins suggests that this association is driven by non-shared environmental factors; and that such association could be the result of in utero impacts on DNA methylation. Here, we present data on the association between the prenatal environment (as indexed by BW), DNA methylation and brain processes in MZ twins.

Materials and Methods: 52 adolescent and 12 newborn MZ twin pairs with various levels of BW discordance were tested. DNA methylation was obtained from mouth swabs at 1 month (newborns) and at age 15 years (adolescents) and assessed with the Illumina Infinium HumanMethylation450 BeadChip Kit. In addition to measures of behaviour and family environment collected in both twin samples, adolescent twins underwent an fMRI at age 15.

Results: In adolescent MZ twins, BW discordance was associated with discordance in cortical morphology. Genes involved in neurodevelopment were tentatively identified as mediators of the BW-cortical volume and BW-cortical surface area relationships. Lower BW twins also had less efficient limbic network resting state connectivity as compared to their higher BW co-twin, which was driven by differences in efficiency for the right hippocampus and right amygdala. DNA methylation as assessed across the genome did not mediate these BW-resting state connectivity associations. We also found in the adolescent twins that discordance in DNA methylation in the serotonin transporter (SLC6A4) gene, a gene important for emotion regulation, was linked to discordance in frontal-limbic neural responses to negative stimuli. Preliminary analyses of the newborn twin data showed that intrapair methylation variation was lower than in adolescent twins, but (as in adolescents) organized in certain functional gene pathways. Intriguingly, 23 functionally relevant probes were differentially methylated as a function of BW discordance in both the adolescent and newborn twins.

Conclusions: The association between BW and cortical morphology in adolescence appears to be attributable to in utero environmental effects, and DNA methylation may play a role in mediating this relationship. An epigenetic-imaging study in young twins is ongoing to study whether impacts of in utero environment on early development are similar to its impacts in adolescence. Such research will inform the design and optimum timing of early preventive interventions to reduce risk for health problems.

Authors

• Linda Booij, Concordia University
  Presenting Author

• Frank Vitaro, University of Montreal
  Non-Presenting Author

• Mara Brendgen, University of Quebec at Montreal
  Non-Presenting Author

• Ginette Dionne, Laval University
  Non-Presenting Author

• Moshe Szyf, McGill University
  Non-Presenting Author

• Michel Boivin, Laval University
  Non-Presenting Author

• Richard Ernest Tremblay, University of Montreal
  Non-Presenting Author