Abstract
BackgroundIdentifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with age-related neurodegeneration.MethodsA gene co-expression network was constructed using data obtained from the Allen Brain Atlas for multiple brain regions (cerebral cortex, cerebellum, and brain stem) in six individuals. Gene network analyses were seeded with 52 reproducible (i.e., established) AD (RAD) genes. Genome-wide association study summary data were integrated with the gene co-expression results and phenotypic information (i.e., memory and aging-related outcomes) from gene knockout studies in Drosophila to generate rankings for other genes that may have a role in AD.ResultsWe found that co-expression of the RAD genes is strongest in the cortical regions where neurodegeneration due to AD is most severe. There was significant evidence for two novel AD-related genes including EPS8 (FDR p = 8.77 × 10−3) and HSPA2 (FDR p = 0.245).ConclusionsOur findings indicate that AD-related risk factors are potentially associated with brain region-specific effects on gene expression that can be detected using a gene network approach.
Highlights
Identifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with agerelated neurodegeneration
In addition to identifying several novel biologically relevant genes for AD, we show that the strength of the correlations among previously established AD genes increases when the networks are restricted to the sub-regions of the brain that are most impacted by AD
The principal component analysis revealed a potential batch effect in the six brain samples with respect to the gene expression in the three high-level brain structures (Fig. 1), noting that this analysis does not account for the non-independent gene co-expression
Summary
Identifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with agerelated neurodegeneration. Neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis, impair or damage neurons. Regional specificity is evident by longitudinal patterning of the AD-related tau and amyloid-β proteins that aggregate into neurofibrillary tangles and senile plaques, respectively [10]. Amyloid plaques form in the opposite pattern, beginning primarily in the outer cortex and spreading inward and to the brain stem [10]. Very few protein aggregates form in the cerebellum even at the most severe stages of AD
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