Document Detail


Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks.
MedLine Citation:
PMID:  22865056     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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;
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Brain imaging and behavior     Volume:  6     ISSN:  1931-7565     ISO Abbreviation:  Brain Imaging Behav     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-28     Completed Date:  2013-08-02     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  101300405     Medline TA:  Brain Imaging Behav     Country:  United States    
Other Details:
Languages:  eng     Pagination:  634-48     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Alzheimer Disease / genetics*
Brain / physiopathology*
Chromosome Mapping / methods*
Cohort Studies
Female
Genetic Predisposition to Disease / genetics
Humans
Male
Middle Aged
Mild Cognitive Impairment / genetics*
Nerve Tissue Proteins / genetics*
Neural Networks (Computer)
Proteome / genetics*
Signal Transduction / genetics*
Grant Support
ID/Acronym/Agency:
K01 AG030514/AG/NIA NIH HHS; P30 AG010129/AG/NIA NIH HHS; P30 AG010133/AG/NIA NIH HHS; P30 AG10133/AG/NIA NIH HHS; R01 AG019771/AG/NIA NIH HHS; R01 AG029672/AG/NIA NIH HHS; R01 AG029672/AG/NIA NIH HHS; R01 AG19771/AG/NIA NIH HHS; R13 AG030995/AG/NIA NIH HHS; R13 AG030995/AG/NIA NIH HHS; R25 CA117865/CA/NCI NIH HHS; RC2 AG036535/AG/NIA NIH HHS; U01 AG024904/AG/NIA NIH HHS; U01 AG024904/AG/NIA NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Nerve Tissue Proteins; 0/Proteome
Investigator
Investigator/Affiliation:
Michael Weiner / ; Paul Aisen / ; Michael Weiner / ; Paul Aisen / ; Ronald Petersen / ; Clifford R Jack / ; William Jagust / ; John Q Trojanowki / ; Arthur Toga / ; Laurel Beckett / ; Robert C Green / ; Andrew J Saykin / ; John Morris / ; Enchi Liu / ; Robert C Green / ; Tom Montine / ; Ronald Petersen / ; Paul Aisen / ; Anthony Gamst / ; Ronald G Thomas / ; Michael Donohue / ; Sarah Walter / ; Devon Gessert / ; Tamie Sather / ; Laurel Beckett / ; Danielle Harvey / ; Anthony Gamst / ; Michael Donohue / ; John Kornak / ; Clifford R Jack / ; Dale Anders / ; Matthew Bernstein / ; Joel Felmlee / ; Nick Fox / ; Paul Thompson / ; Norbert Schuff / ; Gene Alexander / ; Charles DeCarli / ; William Jagust / ; Dan Bandy / ; Robert A Koeppe / ; Norm Foster / ; Eric M Reiman / ; Kewei Chen / ; Chet Mathis / ; John Morris / ; Nigel J Cairns / ; Lisa Taylor-Reinwald / ; J Q Trojanowki / ; Les Shaw / ; Virginia M Y Lee / ; Magdalena Korecka / ; Arthur W Toga / ; Karen Crawford / ; Scott Neu / ; Andrew J Saykin / ; Tatiana M Foroud / ; Steven Potkin / ; Li Shen / ; Zaven Kachaturian / ; Richard Frank / ; Peter J Snyder / ; Susan Molchan / ; Jeffrey Kaye / ; Joseph Quinn / ; Betty Lind / ; Sara Dolen / ; Lon S Schneider / ; Sonia Pawluczyk / ; Bryan M Spann / ; James Brewer / ; Helen Vanderswag / ; Judith L Heidebrink / ; Joanne L Lord / ; Ronald Petersen / ; Kris Johnson / ; Rachelle S Doody / ; Javier Villanueva-Meyer / ; Munir Chowdhury / ; Yaakov Stern / ; Lawrence S Honig / ; Karen L Bell / ; John C Morris / ; Beau Ances / ; Maria Carroll / ; Sue Leon / ; Mark A Mintun / ; Stacy Schneider / ; Daniel Marson / ; Randall Griffith / ; David Clark / ; Hillel Grossman / ; Effie Mitsis / ; Aliza Romirowsky / ; Leyla deToledo-Morrell / ; Raj C Shah / ; Ranjan Duara / ; Daniel Varon / ; Peggy Roberts / ; Marilyn Albert / ; Chiadi Onyike / ; Stephanie Kielb / ; Henry Rusinek / ; Mony J de Leon / ; Lidia Glodzik / ; Susan De Santi / ; P Murali Doraiswamy / ; Jeffrey R Petrella / ; R Edward Coleman / ; Steven E Arnold / ; Jason H Karlawish / ; David Wolk / ; Charles D Smith / ; Greg Jicha / ; Peter Hardy / ; Oscar L Lopez / ; MaryAnn Oakley / ; Donna M Simpson / ; Anton P Porsteinsson / ; Bonnie S Goldstein / ; Kim Martin / ; Kelly M Makino / ; M Saleem Ismail / ; Connie Brand / ; Ruth A Mulnard / ; Gaby Thai / ; Catherine Mc-Adams-Ortiz / ; Kyle Womack / ; Dana Mathews / ; Mary Quiceno / ; Ramon Diaz-Arrastia / ; Richard King / ; Myron Weiner / ; Kristen Martin-Cook / ; Michael DeVous / ; Allan I Levey / ; James J Lah / ; Janet S Cellar / ; Jeffrey M Burns / ; Heather S Anderson / ; Russell H Swerdlow / ; Liana Apostolova / ; Po H Lu / ; George Bartzokis / ; Daniel H S Silverman / ; Neill R Graff-Radford / ; Francine Parfitt / ; Heather Johnson / ; Martin R Farlow / ; Ann Marie Hake / ; Brandy R Matthews / ; Scott Herring / ; Christopher H van Dyck / ; Richard E Carson / ; Martha G MacAvoy / ; Howard Chertkow / ; Howard Bergman / ; Chris Hosein / ; Sandra Black / ; Bojana Stefanovic / ; Curtis Caldwell / ; Ging-Yuek Robin Hsiung / ; Howard Feldman / ; Benita Mudge / ; Michele Assaly / ; Andrew Kertesz / ; John Rogers / ; Dick Trost / ; Charles Bernick / ; Donna Munic / ; Diana Kerwin / ; Marek-Marsel Mesulam / ; Kristina Lipowski / ; Chuang-Kuo Wu / ; Nancy Johnson / ; Carl Sadowsky / ; Walter Martinez / ; Teresa Villena / ; Raymond Scott Turner / ; Kathleen Johnson / ; Brigid Reynolds / ; Reisa A Sperling / ; Keith A Johnson / ; Gad Marshall / ; Meghan Frey / ; Jerome Yesavage / ; Joy L Taylor / ; Barton Lane / ; Allyson Rosen / ; Jared Tinklenberg / ; Marwan Sabbagh / ; Christine Belden / ; Sandra Jacobson / ; Neil Kowall / ; Ronald Killiany / ; Andrew E Budson / ; Alexander Norbash / ; Patricia Lynn Johnson / ; Thomas O Obisesan / ; Saba Wolday / ; Salome K Bwayo / ; Alan Lerner / ; Leon Hudson / ; Paula Ogrocki / ; Evan Fletcher / ; Owen Carmichael / ; John Olichney / ; Charles DeCarli / ; Smita Kittur / ; Michael Borrie / ; T-Y Lee / ; Rob Bartha / ; Sterling Johnson / ; Sanjay Asthana / ; Cynthia M Carlsson / ; Steven G Potkin / ; Adrian Preda / ; Dana Nguyen / ; Pierre Tariot / ; Adam Fleisher / ; Stephanie Reeder / ; Vernice Bates / ; Horacio Capote / ; Michelle Rainka / ; Douglas W Scharre / ; Maria Kataki / ; Earl A Zimmerman / ; Dzintra Celmins / ; Alice D Brown / ; Godfrey D Pearlson / ; Karen Blank / ; Karen Anderson / ; Andrew J Saykin / ; Robert B Santulli / ; Eben S Schwartz / ; Kaycee M Sink / ; Jeff D Williamson / ; Pradeep Garg / ; Franklin Watkins / ; Brian R Ott / ; Henry Querfurth / ; Geoffrey Tremont / ; Stephen Salloway / ; Paul Malloy / ; Stephen Correia / ; Howard J Rosen / ; Bruce L Miller / ; Jacobo Mintzer / ; Crystal Flynn Longmire / ; Kenneth Spicer / ; Elizabether Finger / ; Irina Rachinsky / ; John Rogers / ; Andrew Kertesz / ; Dick Drost /
Comments/Corrections

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