DNA methylation in the central nucleus of the amygdala contributes to anxious temperament in young primates. R. S. Alisch1, P. Chopra1, A. S. Fox1, K. Chen2, A. T. J. White1, P. H. Roseboom1, S. Keles2, N. H. Kalin1 1) Dept. of Psychiatry, Univ. of Wisconsin SMPH, Madison, WI; 2) Dept. of Statistics, Univ. of Wisconsin, Madison, WI.

   Considerable evidence demonstrates that children with an anxious temperament (AT) are at a substantially increased risk to develop anxiety and depression. A validated non-human primate model of AT revealed that the critical neural components underlying AT (e.g. the central nucleus of the amygdala, CeA) differ in their level of heritability, suggesting a role for epigenetics in the expression of this at risk phenotype. Here, we profiled 5-methylcytosine in the CeAs of rhesus monkeys (N = 23) fully phenotyped for AT and identified 5,489 CpG sites (1,363 genes) with methylation levels predictive of individual differences in AT (FDR p-value < 0.05), including genes previously implicated in psychiatric-related disorders (e.g. GRIN1, GRM5, HTT, ADCYAP1, and SHANK3). To further link these genes to function, we examined the CeA gene expression data from these same monkeys and found that AT-associated methylation patterns in twenty-two genes were also correlated with gene expression (p-value < 0.05), including the glutamate receptors, GRIN1 and GRM5. Of these twenty-two genes, BCL11A and JAG1 had expression levels that also significantly predicted AT (p-value < 0.05). These transcripts have well-defined roles in neurodevelopmental processes, including axon branching and dendrite outgrowth (BCL11A) and the regulation of astrogenesis and neurogenesis (JAG1). Together, these data highlight genes of importance in the expression of the early life risk to develop anxiety and depression and implicate epigenetic mechanisms involved in modifying the function of the CeA, a core neural substrate of AT.

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