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Inter-individual variation in patterns of DNA methylation at birth can be explained by the influence of environmental, genetic and stochastic factors. This study investigates the genetic and non-genetic determinants of variation in DNA methylation in human infants. Given its central role in provision of methyl groups for DNA methylation, this study focuses on aspects of folate metabolism. Global (LUMA) and gene specific ( IGF2, ZNT5, IGFBP3 ) DNA methylation were quantified in 430 infants by Pyrosequencing®. Seven polymorphisms in 6 genes ( MTHFR, MTRR, FOLH1, CβS, RFC1, SHMT ) involved in folate absorption and metabolism were analysed in DNA from both infants and mothers. Red blood cell folate and serum vitamin B 12  concentrations were measured as indices of vitamin status. Relationships between DNA methylation patterns and several covariates viz. sex, gestation length, maternal and infant red cell folate, maternal and infant serum vitamin B 12 , maternal age, smoking and genotype were tested. Length of gestation correlated positively with  IGF2  methylation (rho = 0.11,  p  = 0.032) and inversely with  ZNT5  methylation (rho = −0.13,  p  = 0.017). Methylation of the  IGFBP3  locus correlated inversely with infant vitamin B 12  concentration (rho = −0.16,  p  = 0.007), whilst global DNA methylation correlated inversely with maternal vitamin B 12  concentrations (rho = 0.18,  p  = 0.044). Analysis of common genetic variants in folate pathway genes highlighted several associations including infant  MTRR  66G>A genotype with DNA methylation (χ 2  = 8.82,  p  = 0.003) and maternal  MTHFR  677C>T genotype with  IGF2  methylation (χ 2  = 2.77,  p  = 0.006). These data support the hypothesis that both environmental and genetic factors involved in one-carbon metabolism influence DNA methylation in infants. Specifically, the findings highlight the importance of vitamin B 12  status, infant  MTRR  genotype and maternal  MTHFR  genotype, all of which may influence the supply of methyl groups for DNA methylation. In addition, gestational length appears to be an important determinant of infant DNA methylation patterns.

Genetic and Non-Genetic Influences during Pregnancy on Infant Global and Site Specific DNA Methylation: Role for Folate Gene Variants and Vitamin B12