Hippocampal transcriptome-wide association analysis of shared genetic risks between posttraumatic stress disorder and Alzheimer's disease

Background The etiopathogenesis of Alzheimer's disease (AD) is puzzled by the heterogeneous nature of this neurodegenerative disorder. In recent years, clinical and basic research has accentuated a relationship between post-traumatic stress disorder (PTSD) and AD risk. Despite several pathways related to neuroinflammation, metabolic disturbances, and stress, emerging evidence implicates genetic risks at the nexus of PTSD and AD. However, the shared susceptibility genes and potential polygenic overlap between the two conditions is relatively understudied. Objective This study aims to assess the shared genetic risk between AD and PTSD by leveraging large-scale genomic sequencing data through hippocampus-specific transcriptome-wide association studies (TWAS). Methods We focused on a shared vulnerable brain region between AD and PTSD, the hippocampus, to investigate shared genetic risks between the two brain disorders. Functional annotation for TWAS-identified cross-disease susceptibility genes was performed to identify AD/PTSD-related biological pathways. Results FUSION TWAS analysis identified 120 susceptibility genes common to both disorders at the nominal significance of 0.05. Further functional annotation uncovered multiple pivotal biological pathways, especially those related to cell metabolism. Metabolic pathway analysis topped lipid metabolism-related pathways such as “acyl-CoA hydrolysis” that overlaps AD and PTSD risk. Deregulation of these common susceptibility genes in the hippocampus may potentiate PTSD and AD in sequence through hippocampal dysmetabolism. Conclusions These preliminary findings from computational analysis shed light on the genetic association between AD and PTSD, which will endorse further investigation through experimental approaches for a better understanding of the link between the two conditions from a perspective of precision medicine.