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.
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Because this was a smaller subgroup analysis of older, white non-Hispanic decedents, we dropped the seven cell type variables from the path model so as not to overfit the model. None of the cell type variables were significantly associated with KL expression in motor cortex in the multiple regression models (Table 3).
The path model fit the data well per standard fit indices: Χ2 (1, n = 43) = 0.17, p = 0.68, root mean square error of approximation < 0.001, standardized root mean square residual = 0.012, confirmatory fit index = 1.00, Tucker-Lewis index = 2.057. The model was estimated with maximum likelihood estimation.
The brain bank RNA sequence data did not have coverage of this transcript thus we were unable to examine this ncRNA in the brain bank data directly.
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The Traumatic Stress Brain Research Group are Matthew Friedman, M.D., Ph.D.—PTSD BB, Director, Neil Kowall, M.D., PI, VABBB Director, Christopher Brady, Ph.D., Co-I, VABBB Director of Scientific Operations, Ann McKee, M.D., Chief Neuropathologist, Thor Stein, M.D., Ph.D., Neuropathologist, BRH, M.D., Ph.D., Neuropathologist, Victor Alvarez, M.D., Neuropathologist, David Benedek, M.D., Director VA PTSD BB Assessment Core, Robert J. Ursano, MD, Director Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University, Douglas Williamson, PhD, Site Director, Dianne Cruz, M.S., Co-investigator, Keith Young, PhD, Senior Advisor, Ronald Duman, PhD, Director VA PTSD BB Intramural Research Program, John Krystal, MD, Chair Department of Psychiatry, Deborah Mash, MD, Director, Brain Bank, Melanie Hardegree, RN, Co-Investigator, William Scott, Ph.D. Executive Director of the UM Brain Endowment Bank, David Davis Ph.D UM Brain Endowment Bank, Matthew Girgenti Ph.D., Co-Investigator., Brian Marx, PhD, Deputy Director, National Center for PTSD, Behavioral Science Division and Professor of Psychiatry, Boston University School of Medicine and Paul Holtzheimer, MD, Deputy Director for Research, National Center for PTSD and Associate Professor of Psychiatry and Surgery, Geisel School of Medicine at Dartmouth.
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Wolf, E.J., Chen, CD., Zhao, X. et al. Klotho, PTSD, and advanced epigenetic age in cortical tissue. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00884-5