Genomewide pathway analysis of memory impairment

Authors: 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 C Petersen Michael W Weiner Andrew J Saykin for the Alzheimer’s Disease Neuroimaging Initiative ADNI

Publish Date: 2012/08/03

Volume: 6, Issue: 4, Pages: 634-648

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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 genomewide 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 itemlevel data from the ADNI neuropsychological test battery Using the GSASNP software tool we identified 27 canonical expertlycurated pathways with enrichment FDRcorrected pvalue 005 against this composite memory score Processes classically understood to be involved in memory consolidation such as neurotransmitter receptormediated calcium signaling and longterm potentiation were highly represented among the enriched pathways In addition pathways related to cell adhesion neuronal differentiation and guided outgrowth and glucose and inflammationrelated signaling were also enriched Among genes that were highlyrepresented 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 colocalized expression in normal brain tissue along with known AD risk genes These results 1 demonstrate that psychometricallyderived 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 interventionsData used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative ADNI database http//wwwadniloniuclaedu/ As such the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report A complete listing of ADNI investigators can be found at http//adniloniuclaedu/wpcontent/uploads/how to apply/ADNI Acknowledgement Listpdf/Data collection and sharing for this project was funded by the Alzheimer’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’s Association Alzheimer’s Drug Discovery Foundation Amorfix Life Sciences Ltd AstraZeneca Bayer HealthCare BioClinica Inc Biogen Idec Inc BristolMyers Squibb Company Eisai Inc Elan Pharmaceuticals Inc Eli Lilly and Company F HoffmannLa Roche Ltd and its affiliated company Genentech Inc GE Healthcare Innogenetics NV 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 wwwfnihorg The grantee organization is the Northern California Institute for Research and Education and the study is coordinated by the Alzheimer’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 IIS1117335 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

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