A genetic exploration of the relationships between post-traumatic stress disorder and cardiovascular disease

Experiencing a traumatic event may lead to Posttraumatic Stress Disorder (PTSD), including symptoms such as flashbacks and hyperarousal. Individuals suffering from PTSD are at increased risk of cardiovascu- lar disease (CVD), but it is unclear why. This study assesses shared genetic liability and potential causal pathways between PTSD and CVD. We leveraged summary-level data of genome-wide association studies (PTSD: N= 1,222,882; atrial fibril- lation (AF): N=482,409; coronary artery disease (CAD): N=1,165,690; hypertension: N=458,554; heart failure (HF): N=977,323). First, we estimated genetic correlations and utilized genomic structural equation modeling to identify a common genetic factor for PTSD and CVD. Next, we assessed biological, behavioural, and psychosocial factors as potential mediators. Finally, we employed multivariable Mendelian randomiza- tion to examine causal pathways between PTSD and CVD, incorporating the same potential mediators. Significant genetic correlations were found between PTSD and CAD, HT, and HF (rg =0.21-0.32, p < 3.08 x 10−16), but not between PTSD and AF. Insomnia, smoking, alcohol dependence, waist-to-hip ratio, and inflammation (IL6, C-reactive protein) partly mediated these associations. Mendelian randomization indicated that PTSD causally increases CAD (IVW OR=1.53, 95% CIs=1.19-1.96, p=0.001), HF (OR=1.44, CIs=1.08-1.92, p=0.012), and to a lesser degree hypertension (OR=1.25, CIs=1.05-1.49, p=0.012). While insomnia, smoking, alcohol, and inflammation were important mediators, independent causal effects also remained. In addition to shared genetic liability between PTSD and CVD, we present strong evidence for causal effects of PTSD on CVD. Crucially, we implicate specific lifestyle and biological mediators (insomnia, substance use, inflammation) which has important implications for interventions to prevent CVD in PTSD patients. ### Competing Interest Statement RP is paid for his editorial work on the journal Complex Psychiatry and received a re- searchgrant outside the scope of this study from Alkermes. The other authors report no conflict of interest. ### Funding Statement EL, RRV, and JLT are supported by a Senior Scientist Dekker Grant from the Dutch Heart Foundation (project number 03-004-2022-0055). JLT is supported by a European Research Council (ERC) Starting grant (UNRAVEL-CAUSALITY, grant number 101076686) and by Foundation Volksbond Rotterdam. RP is supported by grants from the National Insti- tutes of Health (RF1 MH132337 and R33DA047527) and One Mind. G.A.P. acknowledges support from the Yale Biological Sciences Training Program (T32 MH014276), Alzheimer's Association (AARF-22-967171), NIH National Institute of Aging (K99AG078503), and the Yale Franke Fellowship in Science & Humanities. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Genome-wide association study summary statistics where partly obtained by contacting respective authors I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Facilitated GWAS summary statistics were obtained from online resources or through respective GWAS authors