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

• Published in: Brain imaging and behavior Vol. 6; no. 4; pp. 634 - 648
• Main Authors: Ramanan, Vijay K., Kim, Sungeun, Holohan, Kelly, Shen, Li, Nho, Kwangsik, Risacher, Shannon L., Foroud, Tatiana M., Mukherjee, Shubhabrata, Crane, Paul K., Aisen, Paul S., Petersen, Ronald C., Weiner, Michael W., Saykin, Andrew J.
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01-12-2012; Springer Nature B.V
• Subjects: ADNI: Friday Harbor 2011 Workshop SPECIAL ISSUE; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer's disease; Biomedical and Life Sciences; Biomedicine; Brain - physiopathology; Chromosome Mapping - methods; Cognitive ability; Cognitive Dysfunction - genetics; Cohort Studies; Disease; Female; Genes; Genetic Predisposition to Disease - genetics; Genomes; Genotype & phenotype; Humans; Male; Medical imaging; Medicine; Memory; Middle Aged; Nerve Tissue Proteins - genetics; Neural Networks (Computer); Neuroimaging; Neuropsychology; Neuroradiology; Neurosciences; Proteome - genetics; Psychiatry; Quantitative psychology; Signal Transduction - genetics; San Francisco California; California; Indiana; United States > US; Indianapolis Indiana; Pathway analysis; Psychometrics; Alzheimer’s disease; Genome-wide association study; Mild cognitive impairment; Memory
• ISSN: 1931-7557; 1931-7565
• DOI: 10.1007/s11682-012-9196-x

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.