Genome-wide pathway analysis of memory impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks

Abstract

Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0.05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) demonstrate that psychometrically-derived composite memory scores are an effective phenotype for genetic investigations of memory impairment and 2) highlight the promise of pathway analysis in elucidating key mechanistic targets for future studies and for therapeutic interventions.

Characterizing Gene and Protein Crosstalks in Subjects at Risk of Developing Alzheimer’s Disease: A New Computational Approach

“…Similarly, the enrichment of metabolic pathways, organismal systems including nervous and immune system pathways, and common signaling pathways of the environmental information processing category is also expected and well-supported in the literature [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Interestingly, several genetic information processing pathways, including cell cycle regulation and DNA replication and repair, were found to be enriched.…”

Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

“…Previous Results from Pathway Analysis of AD GWAS Prior to this study, six pathway analyses of AD GWAS have been reported with five studies using the KEGG database [4][5][6][7][8][9]. We compared our findings with the previous pathway analyses of AD GWAS.…”

“…We compared our findings with the previous pathway analyses of AD GWAS. All of the pathway analysis results were publicly available from the original studies [4][5][6][7][8][9].…”

“…A large proportion of AD heritability has yet to be explained. Fortunately, the existing large-scale GWAS datasets provide strong support for the investigation of AD mechanisms using pathway analysis methods [4][5][6][7][8][9].…”

“…We identified cell adhesion molecules (CAM) as a consistent signal in AD. Recently, Ramanan et al [8] performed a pathway enrichment analysis on GWAS data from the 742 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. They confirmed the involvement of CAM in AD (P=5.60E−04) [8].…”