Introduction: Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies.
Methods: We performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses.
Results: We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations.
Discussion: We demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases.
Keywords: MS4A gene family; PTSD; genetic pleiotropy; inflammation and immune-based pathways and Alzheimer's disease; late-onset Alzheimer's disease; posttraumatic stress disorder.
© 2020 the Alzheimer's Association.