title: 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.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Ramanan
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.forename: Kelly
authors.initials: K
authors.lastname: Holohan
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000503:physiopathology*; D002874:Chromosome Mapping / Q000379:methods*; D060825:Cognitive Dysfunction / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016571:Neural Networks, Computer; D020543:Proteome / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D020543:Proteome