"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.

Keywords: Type 2 diabetes mellitus; candidate gene; cardiovascular disease; post traumatic stress disorder.

Figure 1

Functional relationships among 83 candidate PTSD genes. (A) Top canonical pathways. Two top signaling pathways are G-Protein Coupled Receptor and Serotonin Receptor signaling. (B) Associated network Function #1. CREB and PKC are top hubs in this network. (C) Inset: Network #1, top 5 hubs. (D) Associated network Function #2. ERK1/2, AKT, ERK, and p38MAPK are top hubs in this network. (E) Inset: Network #2, top 5 hubs.

Figure 2

Upstream regulation of risk genes for PTSD. (A) Predicted Top Five Upstream Regulators. The top two are NR3C1 (Glucocorticoid Receptor) and TNFα. (B) Predicted Targets of top two upstream regulator, NR3C1 (Glucocorticoid Receptor) and TNFα. (C) Predicted Top Tox (icology) Functions. Top tox function is cardiac hypertrophy.

Figure 3

Functional relationship among 36 candidate PTSD genes, which share an independent risk factor status with cardiovascular disease. (A) Top canonical pathways. The top signaling pathway is Role of Cytokines in Mediating Communication between Immune Cells. (B) Associated Network Function #1. The top hub is TNFalpha, (C) Inset: Network #1, top 5 hubs. (D) Associated Network Function #2. The top hubs are IL-1β, IL-2, p38MAPK, and ERK1/2. (E) Inset: Network #2, top 5 hubs.

Figure 4

Upstream regulation of risk genes for CVD. (A) Predicted Top upstream Regulators. The top two are NLRP12 and TNFa. (B) Predicted Targets of top two upstream regulator, NLRP12 and TNFa. (C) Predicted Top Tox (icology) Functions. All five describe cardiac disease.

Figure 5

Functional relationship among 15 candidate T2DM genes, which share an independent risk factor status with PTSD. (A) Top canonical pathways. The top signaling pathway is Acute Phase Response Signaling. (B) Associated Network Function #1. The top hubs are IL-6, ERK1/2, ERK, and AKT. (C) Inset: Network #1, top 5 hubs. (D) Associated network Function #2. The top hubs are TNFα, IL-1β and IL-12. (E) Inset: Network #2, top 5 hubs.

Figure 6

Upstream regulation of risk genes for T2DM. (A) Predicted Top Upstream Regulators. The top two are LXRA and LXRB. (B) Predicted targets of the top upstream regulator, LXRB. (C) Predicted Top Tox (icology) Lists. The emphasisis on cardiac disease.

Figure 7

NFkB Complex is the focus of principal hubs for PTSD and CVD risk genes. The NFkB Complex is identified specifically by the IPA algorithm to include the cytosolic inhibitors [NFκB, p105] and [IκBα], and the driver [NFκB, p65]. Numbers attached to each arrow are example references from the experimental literature, which document activator functions (arrows) or inhibitor functions (T-endings) between genes. Many of the NFkB-driven genes also interact with each other. When making predictions regarding mechanism, the IPA algorithm takes these interactions into account by reference to its “master” network of information from the Ingenuity Knowledge Base. The numbers correspond to the following references. 28. Wang et al., ; Wen et al., ; 29. Saperstein et al., ; 30. Shirakawa and Mizel, ; 31. Chiang et al., ; 33. Kim et al., ; 34. King et al., ; 35. Shirakawa et al., ; 36. Zhou et al., ; 37. Gonzalez et al., ; 38. Takeuchi and Fukunaga, ; 39. Nair and Sealfon, ; 40. Li et al., ; 41. Sánchez et al., ; 42. Howlett, ; 43. Gustin et al., ; 44. Gustin et al., ; 45. Chen and Roper, ; 46. Davis et al., ; 47. Wang X. et al., ; 48. Wesche et al., ; 49. Wang V. Y. et al., ; 50. Gao et al., ; 51. Patel et al., ; 52. Maliner-Stratton et al., ; 53. Libermann and Baltimore, ; 54. Liao et al., ; 55. Liu et al., .