Nivard, Michel Guillaume, Jentien Vermeulen, Verweij, Karin, Polimanti, Renato, Lukas, Eva, Pathak, Gita A., Treur, Jorien, Smit, Dirk, and Veeneman, Rada R.
Post-traumatic stress disorder (PTSD) may result from traumatic experiences and presents as recurrent mental states related to the event, memories, dreams or reactions to exposure. Adverse mental effects include impairment of one's worldview and self-awareness, negative emotions such as fear, aggression and guilt. The trauma may trigger insomnia, difficulty focusing on tasks or dangerous behavior. Individuals effected by PTSD experience aforementioned symptoms for a duration exceeding one month and tend to avoid internal and/or external reminders of the event (American Psychiatric Association, 2013). Traumatic events that may cause PTSD include acts or threats of (sexual) violence (e.g. war, physical attacks or abuse, torture), falling victim to criminal acts (e.g. robbery, kidnapping, hostage taking), traffic accidents and (natural) disasters. Similarly, witnessing the man- or disaster- caused passing of others or hearing about traumas or sudden death of loved ones may provoke PTSD (American Psychiatric Association, 2013). While co-morbidity of PTSD and other psychiatric disorders is well-known, there is also an association between PTSD and cardiovascular disease (CVD) (De Hert et al., 2018, Edmondson and Cohen, 2013). Various studies have shown an accumulation of a variety of cardiovascular diseases in PTSD patients, including ischemic heart disease, heart failure and atrial fibrillation (Hargrave et al., 2022). Why PTSD is associated with CVD is not fully understood. One possibility is that PTSD and CVD have shared genetic risk factors. It could also be the case that PTSD acts as a (causal) risk factor for CVD, potentially mediated by biological (e.g. autonomous nervous system dysfunction, increased inflammation), behavioral (e.g. sub- stance abuse, obesity, sleep disturbance) and/or psychosocial (e.g. social isolation) factors. In the other direction, a diagnosis or experience of life- threatening CVD could provoke PTSD (Edmondson and Cohen, 2013). In the current study we will use advanced genetic methods to investigate the nature of the association between the two traits/diseases, focusing on shared genetic and causal explanations. PTSD involves certain physical symptoms which may mediate potential (causal) effects on CVD (Foa et al., 2006), including changes in the immune system and in the central nervous system (CNS). Immunosuppressive consequences of stress are extensively researched in literature, e.g. reviewed by Black (1994) and Reiche et al. (2004). Following stressors, corticotropin- releasing factor (CRF) is released, causing elevated concentration of glucocorticoids (GCs) (Black, 1994). GCs are correlated with prioritization of vital body functions, downregulation of immune response and increasing gluconeogenesis (Foa et al., 2006, McEwen, 2000). While cortisol may help the organism cope with stress in the moment, it may cause redundant in- flammation in the long term (Morey et al., 2015). Another possible underlying mechanism of PTSD symptoms is an alter- ation in neurotrophin (NT) concentrations, a growth-, differentiation and survival factor acting on neurons (László et al., 2019). Furthermore, lower levels of brain-derived neurotrophic factor (BDNF) were seen in clinically depressed individuals (László et al., 2019, Lee et al., 2007). While an extrapolation of these findings to PTSD is tempting, a recent meta-analysis highlights the heterogeneity of BDNF level trends in PTSD patients (Mojtabavi et al., 2020). Because randomized controlled trials are practically and ethically unfeasible for the long-term effects under study, causal questions of PTSD and CVD have thus far remained suggestive. Here, we exploit summary- level data of large genome-wide association studies (GWASs) and apply advanced genetic methods to unravel the complex relationship between PTSD and CVD.