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Record W2102416906 · doi:10.1016/j.jalz.2014.05.1757

Convergent genetic and expression data implicate immunity in Alzheimer's disease

2014· article· en· W2102416906 on OpenAlexaff
Lesley Jones, Jean‐Charles Lambert, Weixin Wang, Seung‐Hoan Choi, Denise Harold, Alexey Vedernikov, Valentina Escott‐Price, Timothy Stone, Alexander Richards, Céline Bellenguez, Carla A. Ibrahim‐Verbaas, Adam C. Naj, Rebecca Sims, Amy Gerrish, Gyungah Jun, Anita L. DeStefano, Joshua C. Bis, Gary W. Beecham, Benjamin Grenier‐Boley, Giancarlo Russo, Tricia A. Thornton‐Wells, Nicola Jones, Albert V. Smith, Vincent Chouraki, Charlene Thomas, M. Arfan Ikram, Diana Zélénika, Badri N. Vardarajan, Chiao‐Feng Lin, Helena Schmidt, Brian W. Kunkle, Melanie Dunstan, Agustı́n Ruiz, Marie‐Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L. Fitzpatrick, Joseph D. Buxbaum, Dominique Campion, Paul K. Crane, Tim Becker, Vilmundur Guðnason, Carlos Cruchaga, David W. Craig, Najaf Amin, Claudine Berr, Oscar L. López, Philip L. De Jager, Vincent Deramecourt, Janet Johnston, Denis A. Evans, Simon Lovestone, Luc Letteneur, Johanes Kornhuber, Lluís Tárraga, David C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison Goate, Nathalie Fiévet, Matthew J. Huentelman, Michael Gill, Valur Emilsson, Kristelle Brown, M. Ilyas Kamboh, Lina Keller, Pascale Barberger‐Gateau, Bernadette McGuinness, Eric B. Larson, Amanda Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Patrick G. Kehoe, Ekaterina Rogaeva, John Gallacher, Peter St George‐Hyslop, Jordi Clarimón, Alberti Lleὀ, Debby W. Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, John Collinge, Sandro Sorbi, Florentino Sánchez-García, Nick C. Fox, John Hardy, María Cándida Déniz Naranjo, Cristina Razquín, Paola Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Michelangelo Mancuso, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, María J. Bullido, Francesco Panza, Paolo Caffarra, Benedetta Nacmias, John R. Gilbert, Manuel Mayhaus, Frank Jessen, Martin Dichgans, Lars Lannfelt, Håkon Håkonarson, Sabrina Pichler, Minerva M. Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alavarez, Fanggeng Zou, Otto Valladares, Steven G. Younkin, Eliécer Coto, Kara L. Hamilton‐Nelson, Ignacio Mateo, Michael J. Owen, Kelley M. Faber, Pálmi V. Jónsson, Onofre Combarros, Michael O‘Donovan, Laura B. Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H. Mosley, David Bennett, Tamara B. Harris, Laura Fratiglioni, Clive Holmes, Renée F.A.G. de Bruijn, Peter Passmore, Thomas J. Montine, Karolien Bettens, Jerome I. Rotter, Alexis Brice, Kevin Morgan, Tatiana Foroud, Walter A. Kukull, Didier Hannequin, John Powell, Michael A. Nalls, Karen Ritchie, Kathryn L. Lunetta, John S.K. Kauwe, Eric Boerwinkle, Merçé Boada, Mikko Hiltunen, Eden R. Martin, Pau Pástor, Reinhold Schmidt, Dan Rujescu, Jean‐François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M. Nöthen, Caroline Graff, Bruce M. Psaty, Jonathan L. Haines, Mark Lathrop, Margaret A. Pericak‐Vance, Lenore J. Launer, Lindsay A. Farrer, Cornelia M. van Duijn, Christine Van Broeckhoven, Alfredo Ramı́rez, Gerard D. Schellenberg, Sudha Seshadri, Philippe Amouyel, Julie Williams, Peter Holmans

Bibliographic record

VenueAlzheimer s & Dementia · 2014
Typearticle
Languageen
FieldMedicine
TopicAlzheimer's disease research and treatments
Canadian institutionsOccupational Cancer Research CentreMcGill University and Génome Québec Innovation CentreUniversity of Toronto
FundersNational Center for Research ResourcesNational Cancer InstituteNational Institute of Mental HealthNational Heart, Lung, and Blood InstituteNational Institutes of HealthAlzheimer’s Research UKFédération pour la Recherche sur le CerveauErasmus Medisch CentrumMedical Research CouncilLabexNational Institute of Neurological Disorders and StrokeNational Institute for Health and Care ResearchInstitut National de la Santé et de la Recherche MédicaleNational Center for Advancing Translational SciencesNational Human Genome Research InstituteAlzheimer's SocietyWellcome TrustNational Institute on AgingAlzheimer's AssociationWellcomeDevelopment of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
KeywordsBiologyGenome-wide association studyDiseaseEndocytosisComputational biologyBiological pathwayGenetic associationImmune systemGeneProteasomeGeneticsFunctional genomicsUbiquitinGenomicsGene expressionBioinformaticsGenomeMedicineCellGenotypeInternal medicineSingle-nucleotide polymorphism

Abstract

fetched live from OpenAlex

BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10(-11)), cholesterol transport (P = 2.96 × 10(-9)), and proteasome-ubiquitin activity (P = 1.34 × 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame machine prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.

metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.002
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.002
Threshold uncertainty score0.008

Distilled classifier scores by category (both heads)

CategoryCodexGemma
Metaresearch0.0010.002
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0010.001
Bibliometrics0.0010.002
Science and technology studies0.0000.001
Scholarly communication0.0010.000
Open science0.0000.001
Research integrity0.0000.001
Insufficient payload (model declined to judge)0.0020.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.054
GPT teacher head0.328
Teacher spread0.274 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations207
Published2014
Admission routes1
Has abstractyes

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