@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 C.} and Weiner, {Michael W.} and Saykin, {Andrew J.}",
note = "Funding Information: Data used for this study were obtained through the ADNI database (http://adni.loni.ucla.edu/). ADNI was launched in 2003 (PI: Michael W. Weiner, MD, VA Medical Center and University of California-San Francisco) with the goal of evaluating biomarkers of AD-related neuropathology in patients with MCI and early AD. This multi-site longitudinal study is supported by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies, and non-profit organizations. Participants in ADNI include older individuals, aged 55–90 years, who were recruited from 59 sites across the United States and Canada. These subjects include approximately 200 cognitively normal patients (CN), 400 patients diagnosed with MCI, and 200 patients diagnosed with early probable AD. As described elsewhere (Jack et al. 2009; Weiner et al. 2010; Aisen et al. 2010), diagnoses of participants were made on a clinical basis (via neuropsychological assessment data and patient and informant reports of cognitive performance and functioning in activities of daily living) at consensus conferences involving neurologists, neuropsychologists, and study coordinators. Written informed consent was obtained for all participants and prior Institutional Review Board approval was obtained at each participating institution. All demographic information, neuropsychological and clinical assessment data, and diagnostic information used in this study were downloaded from the ADNI clinical data repository (http://adni.loni.ucla.edu/). Genotype data used in this study include genome-wide single nucleotide polymorphism (SNP) data obtained from a GWAS on the full ADNI sample (Saykin et al. 2010) and APOE ε4 allele status. Further information about ADNI can be found in (Weiner et al. 2010) and at http://www.adni-info.org/. Funding Information: Acknowledgments Data collection and sharing for this project was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. Data management and the specific analyses reported here were supported by NSF IIS-1117335 (Shen), NIA R13 AG030995 (Mungas), NIA R01 AG19771 (Saykin), P30 AG10133 (Saykin/Ghetti), and R01 AG029672 (Crane). The authors declare that they have no conflict of interest.",
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",
}