“Soldier's Heart”: A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder

Abstract

“Soldier's Heart,” is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test (P = 3 × 10−54). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test (P = 1.8 × 10−16). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation.

Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease

“…Moreover, that study found overlap in the upstream genes (e.g., TNFα, involved in inflammation) that regulated both PTSD- and cardiovascular-associated genes, as well as overlap in their gene targets (e.g., the NfκB complex, also involved in inflammation). This suggests that the genetic link between PTSD and cardiovascular disorders is likely mediated by common genetic effects on the inflammation and immune systems [32]. Consistent with this, Breen et al [33] found that gene networks critical for immune system functioning were associated with PTSD in gene expression data from two samples of military veterans.…”

“…Consistent with this, Sumner et al [31] found that genome-wide risk for PTSD was correlated with genome-wide risk for coronary artery disease, with somewhat weaker evidence for shared genetic risk across PTSD and body mass index and insulin levels. Using an alternate methodology, Pollard et al [32] found overlap between the candidate genes previously associated with PTSD and the candidate genes previously associated with cardiovascular disease and type 2 diabetes. Moreover, that study found overlap in the upstream genes (e.g., TNFα, involved in inflammation) that regulated both PTSD- and cardiovascular-associated genes, as well as overlap in their gene targets (e.g., the NfκB complex, also involved in inflammation).…”

“…Future PTSD brain bank studies could use similar methodology to evaluate mechanisms of PTSD-related accelerated aging in the brain. Specifically, using in situ hybridization and immunohistochemistry, RNA and protein expression of candidates genes implicated in PTSD- and HPA-axis functioning (e.g., CRF , FKBP5 , NR3C1, SKA2 ) [87–91], oxidative stress ( RORA , ALOX12 ) [30••, 92••, 93], and inflammation ( TNFα , CRP ) [32, 74–77], could be compared across brain regions (in both neurons and glia) and the periphery. To discern which cellular elements drive the hypothesized effects on DNAm age, fluorescence activated cell sorting (FACS) could be used to interrogate differential methylation status of the loci in the age algorithms, and reactive oxygen species (ROS) levels, in glia compared to neurons across brain regions.…”

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

“…PTSD is frequently associated with the occurrence of comorbid mental disorders such as major depression 1 and other adverse health sequelae including type 2 diabetes and cardiovascular disease. 2,3 Given this high prevalence and impact, PTSD is a serious public health problem. An understanding of the biological mechanisms of risk for PTSD is therefore an important goal of research ultimately aimed at its prevention and mitigation.…”

Letter to the Editor: Posttraumatic stress disorder has genetic overlap with cardiometabolic traits

“…Additionally, overlapping genetic factors may predispose individuals to both PTSD and cardiometabolic disease. Initial evidence for shared genetic effects across PTSD and cardiometabolic traits comes from studies based on twin designs (Vaccarino et al , 2014, Vaccarino et al , 2013) and candidate gene approaches (Pollard et al , 2016). However, to date, research has not examined the genetic overlap of PTSD and cardiometabolic disease using a genome-wide design.…”