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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 634-648 |
| Number of pages | 15 |
| Journal | Brain Imaging and Behavior |
| Volume | 6 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2012 |
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Keywords
- Alzheimer's disease
- Genome-wide association study
- Memory
- Mild cognitive impairment
- Pathway analysis
- Psychometrics
ASJC Scopus subject areas
- Clinical Neurology
- Psychiatry and Mental health
- Neurology
- Cognitive Neuroscience
- Cellular and Molecular Neuroscience
- Behavioral Neuroscience
- Radiology Nuclear Medicine and imaging
Cite this
Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks. / 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 Carl; Weiner, Michael W.; Saykin, Andrew J.
In: Brain Imaging and Behavior, Vol. 6, No. 4, 2012, p. 634-648.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks
AU - Ramanan, Vijay K.
AU - Kim, Sungeun
AU - Holohan, Kelly
AU - Shen, Li
AU - Nho, Kwangsik
AU - Risacher, Shannon L.
AU - Foroud, Tatiana M.
AU - Mukherjee, Shubhabrata
AU - Crane, Paul K.
AU - Aisen, Paul S.
AU - Petersen, Ronald Carl
AU - Weiner, Michael W.
AU - Saykin, Andrew J.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Genome-wide association study
KW - Memory
KW - Mild cognitive impairment
KW - Pathway analysis
KW - Psychometrics
UR - http://www.scopus.com/inward/record.url?scp=84871715374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871715374&partnerID=8YFLogxK
U2 - 10.1007/s11682-012-9196-x
DO - 10.1007/s11682-012-9196-x
M3 - Article
VL - 6
SP - 634
EP - 648
JO - Brain Imaging and Behavior
JF - Brain Imaging and Behavior
SN - 1931-7557
IS - 4
ER -