Exploring the selective vulnerability in Alzheimer disease using tissue specific variant analysis

The selective vulnerability of distinct regions of the brain is a critical factor in neurodegenerative disorders. In Alzheimer's disease (AD), neurons in hippocampus situated in medial temporal lobe are immensely damaged. Identifying tissue-specific variants is essential in order to perceive the selective vulnerability in AD. In current work, we aligned mRNA-seq data with HG19/HG38 genomic assembly and identified specific variations present in temporal, frontal and other lobes of the AD using sequence alignment map tools. We compared the results with the genome-wide association and gene expression quantitative trait loci studies of the various neurological disorders. We also distinguished variants and epitranscriptomic modifications through the RNA-modification database and evaluated the variant effect in the coding/UTR regions. In addition, we developed genetic and functional interaction networks to understand the relationship between predicted vulnerable variations and differentially expressed genes. We found that genes involved in gliogenesis, intermediate filament organization are altered in the temporal lobe. Oxidative phosphorylation, and calcium ion homeostasis are modified in the frontal lobe, and protein degradation, apoptotic signaling are altered in other lobes. From this study, we propose that disruption of glial cell structural integrity, defective gliogenesis, and failure in glia-neuron communication are the primary factors for selective vulnerability.