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Shared genetic etiology underlying late‐onset Alzheimer’s disease and post traumatic stress syndrome
Author(s) -
Lutz Michael W.,
Luo Sheng,
Williamson Douglas E.,
ChibaFalek Ornit
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041284
Subject(s) - genome wide association study , pleiotropy , anxiety , depression (economics) , disease , genetic load , etiology , genetic association , single nucleotide polymorphism , clinical psychology , medicine , psychology , genetics , gene , psychiatry , biology , population , genotype , macroeconomics , environmental health , economics , phenotype , inbreeding
Background Patients with late‐onset Alzheimer’s Disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms (NPS) with depression and anxiety being most prevalent. Posttraumatic stress disorder (PTSD) is a neuropsychiatric condition that is highly comorbid with depression and anxiety and PTSD patients also have an increased risk for developing dementia. These evidences suggest the possibility of shared etiologies and intersecting pathways between LOAD and PTSD. We investigated genetic pleiotropy between LOAD and PTSD. Method We assessed genetic pleiotropy by using a conditional false discovery rate framework based on GWAS summary statistics: LOAD (IGAP, ADG Consortium study of genetic risk for Alzheimer’s disease in African Americans); PTSD (Psychiatric Genomics Consortium PTSD GWAS (discovery), the Genetic and Environmental Predictors of Combat‐Related PTSD study (replication). Functional bioinformatics and gene expression analysis was completed for genes that replicated in the discovery and replication cohorts. Result We found enrichment of 2.2‐5.6 fold for SNPs associated with LOAD across increasingly stringent levels of significance with PTSD association. The reverse conditional association showed a modest enrichment of approximately 1.3‐5.0 fold. Similar fold enrichment was observed for the African American samples. Six genes were identified as FDR significant for the association with LOAD conditional on PTSD for both the discovery and replication cohorts. Four genes in the MS4 gene family replicated in the two independent PTSD datasets, pointing to a role for genes associated with immunity in the shared genetic signature. These genes showed a shared, consistent expression pattern in the cerebellar hemisphere and cerebellum and a similar expression pattern in the amygdala, hippocampus, cortex and frontal cortex. Cross‐brain‐tissue analysis identified a significant association ( P = 2.9 × 10 −7 ) for the MS4A6A gene. There were no FDR significant results in either direction for the African American dataset. Conclusion Identifying common genetic signatures for LOAD and PTSD advances understanding of shared genetic etiologies and impaired pathways between these conditions. Our data suggest that immune function genes may play a role in both PTSD and LOAD, implicating common pathways. This knowledge provides insights for actionable targets to treat NPS earlier in life to delay or ultimately prevent the onset of LOAD.