Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology
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Abstract
INTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer’s disease (LOAD).
METHODS: We performed transcriptome-wide meta-analysis (N=1,440) of blood-based microarray gene expression profiles as well as neuroimaging and CSF endophenotype analysis.
RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid-β accumulation, especially in the entorhinal cortex region. cis-eQTL mapping analysis of CREB5 detected five significant associations (p<5x10−8), where rs56388170 (most significant) was also significantly associated with global cortical amyloid-β (Aβ) deposition measured by [18F]Florbetapir PET and CSF Aβ1-42.
DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to AD. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity and learning and memory.