Examining the multivariate genetic architectures of posttraumatic stress disorder and cardiovascular disease phenotypes

Abstract

Posttraumatic stress disorder (PTSD) is associated with elevated cardiovascular disease (CVD) risk, but the extent of shared inherited liability is unclear. Large genome‐wide association studies (GWAS) allow for multivariate evaluation of common genetic architecture. We analyzed European‐ancestry GWAS summary statistics for PTSD ( N _eff ≈ 1.22 million), CVD outcomes (CVD _outcomes ; coronary artery disease, stroke, hypertension; N _eff = 126,000–574,000), and CVD risk factors (CVD _risk ; high‐density lipoprotein, triglycerides, fasting glucose, waist circumference; N = 211,000–526,000). Using genomic structural equation modeling, we modeled latent genetic structure across PTSD and CVD phenotypes and conducted multivariate GWAS of latent factors with gene and gene‐set annotation. A three‐factor model distinguishing PTSD, CVD _risk , and CVD _outcomes best fit the data, χ ² = 256.9, CFI = .990, SRMR = .040. PTSD showed a moderate genetic correlation with CVD _risk , rg = .340, p < .001, and a significant but negligible genetic correlation with CVD _outcomes , rg = 0.030, p < .001, suggesting minimal shared genetic liability at the latent‐factor level. Multivariate GWAS identified seven loci for PTSD, 96 for CVD _risk , and 51 for CVD _outcomes . Gene‐based tests implicated 85, 910, and 390 genes, respectively, with 18 overlapping between PTSD and CVD _risk . Enrichment highlighted RNA metabolism for PTSD and lipid/vascular pathways for CVD traits. Additional locus‐level overlaps emerged, including a genomic hub in the major histocompatibility complex region on Chromosome 6 for both phenotypes. PTSD shares moderate polygenic overlap with CVD, particularly CVD _risk , but many loci are trait‐specific, implicating lipid metabolism, vascular tone, immune/inflammatory pathways, and RNA regulation as potential links.