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

Vijay K. Ramanan, Sungeun Kim, Kelly Holohan, Li Shen, Kwangsik Nho, Shannon L. Risacher, Tatiana M. Foroud, Shubhabrata Mukherjee, Paul K. Crane, Paul S. Aisen, Ronald Carl Petersen, Michael W. Weiner, Andrew J. Saykin

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)634-648
Number of pages15
JournalBrain Imaging and Behavior
Volume6
Issue number4
DOIs
StatePublished - 2012

Fingerprint

Neuroimaging
Alzheimer Disease
Genome
Genes
Memory Disorders
Phenotype
Neurotransmitter Receptor
Calcium Signaling
Long-Term Potentiation
Neuropsychological Tests
Genome-Wide Association Study
Psychometrics
Cell Adhesion
Single Nucleotide Polymorphism
Transcription Factors
Software
Inflammation
Glucose
Brain
Therapeutics

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 journalArticle

Ramanan, VK, Kim, S, Holohan, K, Shen, L, Nho, K, Risacher, SL, Foroud, TM, Mukherjee, S, Crane, PK, Aisen, PS, Petersen, RC, Weiner, MW & Saykin, AJ 2012, 'Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks', Brain Imaging and Behavior, vol. 6, no. 4, pp. 634-648. https://doi.org/10.1007/s11682-012-9196-x
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. / Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks. In: Brain Imaging and Behavior. 2012 ; Vol. 6, No. 4. pp. 634-648.
@article{e821a4377b004b65b2464fc0e58c9453,
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.",
keywords = "Alzheimer's disease, Genome-wide association study, Memory, Mild cognitive impairment, Pathway analysis, Psychometrics",
author = "Ramanan, {Vijay K.} and Sungeun Kim and Kelly Holohan and Li Shen and Kwangsik Nho and Risacher, {Shannon L.} and Foroud, {Tatiana M.} and Shubhabrata Mukherjee and Crane, {Paul K.} and Aisen, {Paul S.} and Petersen, {Ronald Carl} and Weiner, {Michael W.} and Saykin, {Andrew J.}",
year = "2012",
doi = "10.1007/s11682-012-9196-x",
language = "English (US)",
volume = "6",
pages = "634--648",
journal = "Brain Imaging and Behavior",
issn = "1931-7557",
publisher = "Springer New York",
number = "4",

}

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

C2 - 22865056

AN - SCOPUS:84871715374

VL - 6

SP - 634

EP - 648

JO - Brain Imaging and Behavior

JF - Brain Imaging and Behavior

SN - 1931-7557

IS - 4

ER -