Differential Epigenetic Regulation of Glutamatergic Synapse Pathway in Adults With Prenatal Exposure to Famine

It has been hypothesized that poor nutrition during prenatal growth may alter the development of vital organs like the brain, thus "program" predisposition to certain diseases later in life, including mental disorders. Although with support from studies using animal models and epidemiologic observations, the biological aspect of the hypothesis has been rarely studied in humans. Using famine as a natural experiment, we explored the altered DNA methylation patterns in genes of the glutamate synapse pathway in whole blood of adults born during the Chinese famine of 1959-1961. We detected significant patterns of hypomethylation for the whole pathway (p = 0.025), for the GRIA1 gene in the AMPA subunit (p = 0.004), for GRM2 (p = 0.023) and GRM3 (p = 0.019) genes in the metabotropic receptor subunit. Our sex-stratified analysis identified significant enrichment of hypomethylation for the overall pathway (p = 0.031), for GRIA1 genes (p = 0.009), GRIA4 gene (p = 0.014), and GRM3 gene (p = 0.031) in females but no significantly enriched pattern in males. Further analysis by location in gene locus found significant enrichment of hypomethylation of the pathway genes in the gene body in sex-combined (p = 0.020) and in female (p = 0.026) samples. In conclusion, our epigenetic association analysis found significantly enriched hypomethylation patterns for the glutamate synapse pathway and for genes in subunits of the pathway, which are more pronounced in female than in male samples prenatally exposed to famine.