The Genetic Relationships Between Post-Traumatic Stress Disorder and Its Corresponding Neural Circuit Structures

Abstract

Post-traumatic stress disorder (PTSD) may be linked to abnormalities in neural circuits that facilitate fear learning and memory processes. The precise degree to which this connection is influenced by genetic factors is still uncertain. This study aimed to investigate the genetic association between PTSD and its corresponding brain circuitry components. We conducted a meta-analysis using the summary of PTSD genome-wide association studies (GWAS) from multiple cohorts to enhance statistical power (sample size = 306,400). Based on the result, and utilizing the lifetime trauma events (LTE) trait as a control for PTSD, we investigated the genetic association of PTSD and LTE with 9 brain structure traits related to the brain circuitry (4 cortical, 2 subcortical, and 3 white matter) by various methodologies, including heritability tissue enrichment analysis, global and local genetic correlations, polygenic overlap analysis, and causal inference. As a result, we discovered the enrichment of heritability for PTSD within circuitry-relevant brain regions such as the cingulate cortex and frontal cortex, and we identified genetic correlations between PTSD and these brain regions. We have observed a polygenic overlap and a total of 31 novel jointly significant genetic loci (conjunction FDR < 0.05). These loci are involved in the process of DNA damage and repair as well as the pathway of neurodegenerative diseases. We also identified a potential causal relationship between PTSD and the surface area of the frontal pole. Our findings offer a valuable understanding of the genetic mechanisms underlying PTSD and its associated brain circuitry.