Intergenerational Effects of Maternal Holocaust Exposure on <i>FKBP5</i> Methylation.

Abstract

There is growing evidence that exposure to trauma prior to conception can affect offspring. The authors have reported that adult offspring of Holocaust survivors showed lower methylation of FK506 binding protein 5 (<i>FKBP5</i>) intron 7, site 6 compared with Jewish comparison volunteers. The present study sought to replicate this finding in a larger sample and to examine parental and offspring correlates of observed effects. Cytosine methylation was measured in blood using pyrosequencing. The independent replication sample consisted of 125 Holocaust offspring and 31 control subjects. Additional analyses, performed in a larger sample of 147 offspring and 40 control subjects that included the 31 previously studied participants, examined associations of parental trauma-related variables (i.e., sex of the exposed parent, parental posttraumatic stress disorder, age at Holocaust exposure) and offspring characteristics (i.e., childhood trauma exposure, lifetime psychiatric diagnoses, psychotropic medication use, <i>FKBP5</i> rs1360780 genotype, <i>FKBP5</i> gene expression, and neuroendocrine measures) with offspring <i>FKBP5</i> methylation. <i>FKBP5</i> site 6 methylation was significantly lower in Holocaust offspring than in control subjects, an effect associated with maternal Holocaust exposure in childhood and with lower offspring self-reported anxiety symptoms. <i>FKBP5</i> gene expression was elevated in Holocaust offspring. <i>FKBP5</i> methylation was associated with indices of glucocorticoid sensitivity but not with basal <i>FKBP5</i> gene expression. This study replicates and extends the previously observed decrement in <i>FKBP5</i> intron 7, site 6 methylation in Holocaust offspring. The predominance of this effect in offspring of mothers exposed during childhood implicates maternal developmental programming as a putative mechanism.