Abstract
Human aging is associated with cognitive decline and an increased risk of neurodegenerative disease. Our objective for this study was to evaluate potential relationships between age and variation in gene expression across different regions of the brain. We analyzed the Genotype-Tissue Expression (GTEx) data from 54 to 101 tissue samples across 13 brain regions in post-mortem donors of European descent aged between 20 and 70 years at death. After accounting for the effects of covariates and hidden confounding factors, we identified 1446 protein-coding genes whose expression in one or more brain regions is correlated with chronological age at a false discovery rate of 5%. These genes are involved in various biological processes including apoptosis, mRNA splicing, amino acid biosynthesis, and neurotransmitter transport. The distribution of these genes among brain regions is uneven, suggesting variable regional responses to aging. We also found that the aging response of many genes, e.g., TP37 and C1QA, depends on individuals' genotypic backgrounds. Finally, using dispersion-specific analysis, we identified genes such as IL7R, MS4A4E, and TERF1/TERF2 whose expressions are differentially dispersed by aging, i.e., variances differ between age groups. Our results demonstrate that age-related gene expression is brain region-specific, genotype-dependent, and associated with both mean and dispersion changes. Our findings provide a foundation for more sophisticated gene expression modeling in the studies of age-related neurodegenerative diseases.
Highlights
Aging is a natural process, and the progression of age has profound impacts on physical and mental health
The data was generated using RNA sequencing (RNA-seq) with tissues initially sampled from two brain regions: cerebellum and cortex, preserved using the PAXgene tissue preservation system (Groelz et al, 2013), and with tissues subsequently sampled from frozen brains in following regions: amygdala, anterior cingulate cortex (BA24), caudate, cerebellar hemisphere, frontal cortex (BA9), hippocampus, hypothalamus, nucleus accumbens, putamen, spinal cord, and substantia nigra (Carithers et al, 2015; GTEx_Consortium, 2015)
The tissue samples were collected from 13 regions of the human brain, namely (1) amygdala, (2) anterior cingulate cortex [Brodmann area 24 (BA24)], (3) caudate, (4) cerebellar hemisphere, (5) cerebellum (PAXgene), (6) cortex (PAXgene), (7) frontal cortex (BA9), (8) hippocampus, (9) hypothalamus, (10) nucleus accumbens, (11) putamen, (12) spinal cord, and (13) substantia nigra
Summary
Aging is a natural process, and the progression of age has profound impacts on physical and mental health. The mechanisms underlying age-related cognitive decline and increased risk of neurodegenerative disease remain unclear, though both decline and disease are universally common; it is critically important to understand the effects of aging on the human brain. One way to approach this goal is to detect the gene expression changes in the human brain during the aging process (Lu et al, 2004). Brain transcriptomic studies hold promise for better understanding the role of aging in both normal brain activity and the development of neurodegenerative disease. The advent of high-throughput sequencing has allowed the study of genome-wide patterns of change in gene expression associated with aging
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