Abstract
BACKGROUND: The development of posttraumatic stress disorder (PTSD) is attributable to the interplay between exposure to severe traumatic events, environmental factors, and biological characteristics. Blood and brain imaging markers have been associated with PTSD. However, to our knowledge, no study has systematically investigated the genetic relationship between PTSD, metabolic biomarkers, and brainwide imaging. METHODS: We integrated genome-wide data informative of PTSD, 233 metabolic biomarkers, and 3935 brain imaging-derived phenotypes (IDPs). Pleiotropy was assessed by applying global and local genetic correlation, colocalization, and genetically inferred causality. RESULTS: We observed significant genetic overlap between PTSD and glycoprotein acetyls (GlycA) (a stable inflammatory biomarker) in 2 independent cohorts (discovery r (g) = 0.26, p = 1.00 × 10(-4); replication r (g) = 0.23, p = 5.99 × 10(-19)). Interestingly, there was no genetic correlation between anxiety and GlycA (p = .33). PTSD and GlycA were both genetically correlated with median T2∗ in the left pallidum (IDP-1444: r (g) = 0.14, p = 1.39 × 10(-5); r (g) = -0.38, p = 2.50 × 10(-3), respectively). Local genetic correlation between PTSD and GlycA was observed in 7 genetic regions (p < 2.0 × 10(-5)), mapping genes related to immune and stress response, inflammation, and metabolic processes. Furthermore, we identified 1 variant, rs12048743, with evidence of horizontal pleiotropy linking GlycA and IDP-1444 (z (IDP-1444) = 17.14, z (GlycA) = -6.07, theta p = 2.06 × 10(-8)). Regional colocalization was observed among GlycA, IDP-1444, and tissue-specific transcriptomic regulation for brain frontal cortex and testis (rs12048743-chr1q32.1; posterior probability > 0.8). While we also tested causality between PTSD, metabolomic biomarkers, and brain IDPs, these were not consistent across different genetically informed causal inference methods. CONCLUSIONS: Our findings highlight a new putative pleiotropic mechanism that links systemic inflammation and pallidum structure to PTSD.