Klotho, PTSD, and advanced epigenetic age in cortical tissue

Abstract

This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42). An evaluation of 211 additional common KL variants revealed that only variants in linkage disequilibrium with rs9315202 showed similarly high levels of significance. Alcohol abuse was nominally associated with advanced epigenetic age in motor cortex (p = 0.039, n = 114). The rs9315202 SNP interacted with PTSD to predict decreased KL expression via DNAm age residuals in motor cortex among older white non-Hispanics decedents (indirect β = -0.198, p = 0.027). Finally, in dual-luciferase enhancer reporter system experiments, we found that inserting the minor allele of rs9315202 in a human kidney cell line HK-2 genomic DNA resulted in a change in KL transcriptional activities, likely operating via long noncoding RNA in this region. This was the first study to examine multiple forms of psychopathology in association with advanced DNA methylation age across several brain regions, to extend work concerning the association between rs9315202 and advanced epigenetic to brain tissue, and to identify the effects of rs9315202 on KL gene expression. KL augmentation holds promise as a therapeutic intervention to slow the pace of cellular aging, disease onset, and neuropathology, particularly in older, stressed populations.

Fig. 1. PTSD is associated with advanced epigenetic age in motor cortex as a function of rs9315202.

The figure shows mean (error bars represent +/−1.96 SE) DNAm age residuals in the motor cortex in the older cohort as a function of PTSD diagnosis and genotype at rs9315202.

Fig. 2. Analysis of the effects of mutation on rs9315202 by a dual-luciferase reporter system in HK-2 cells.

Firefly (FLUC), NLUC coincidence reporter system under control of either KL 4Kb (a) or 1.8 kb (b) promoter. The enhancer activities of WT and rs9315202 T variant (Tovar) constructs were analyzed by dual-luciferase assay.