← Back to cohort
Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing
B K Kunkle, Benjamin Grenier‐Boley, Rebecca Sims, JC Bis, A.C. Naj, Anne Boland, Maria Vronskaya, SJ van der Lee, Alexandre Amlie‐Wolf, Céline Bellenguez, Aura Frizatti, Vincent Chouraki, E. P. SELIGMAN MARTIN, Kristel Sleegers, Nandini Badarinarayan, Jóhanna Jakobsdóttir, K.L. Hamilton‐Nelson, R Aloso, Rachel Raybould, Yong Chen, AB Kuzma, Mikko Hiltunen, Taniesha Morgan, Shahzad Ahmad, BN Vardarajan, Jacques Epelbaum, Per Hoffmann, Merçé Boada, G W Beecham, J-G Garnier, Denise Harold, A.L. Fitzpatrick, Otto Valladares, ML Moutet, Amy Gerrish, A.V. Smith, Liming Qu, Delphine Bacq, Nicola Denning, Xueqiu Jian, Yi Zhao, MD Zompo, NC Fox, ML Grove, Sung‐Hyuk Choi, Ignacio Mateo, JT Hughes, HH Adams, John Malamon, FS Garcia, Yogen Patel, J. A. Brody, Beth A. Dombroski, M.C.D. Naranjo, Makrina Daniilidou, Gudny Eiriksdottir, Shubhabrata Mukherjee, David Wallon, James Uphill, Thor Aspelund, L.B. Cantwell, Fabienne Garzia, Daniela Galimberti, Edith Hofer, M Butkiewics, Bertrand Fin, Elio Scarpini, Chloé Sarnowski, William S. Bush, Stéphane Meslage, Johannes Kornhuber, C. Jackson White, Yeunjoo E. Song, RC Barber, Sebastiaan Engelborghs, Sabrina Pichler, Dina Voijnovic, PM Adams, Rik Vandenberghe, Manuel Mayhaus, L. Adrienne Cupples, Albert Ms, PP De Deyn, Wei Gu, JJ Himali, Duane Beekly, Alessio Squassina, AM Hartmann, Adela Orellana, Deborah Blacker, Eloy Rodríguez‐Rodríguez, Simon Lovestone, M. E. Garcia, R.S. Doody, C.M. Fernadez, Rebecca Sussams, Honghuang Lin, TJ Fairchild, Y.A. Benito, Clive Holmes, Hata Comic, M P Frosch, Håkan Thonberg, W. Maier, G Roschupkin, Bernardino Ghetti, Vilmantas Giedraitis, Amit Kawalia, S Li, RM Huebinger, Lena Kilander, Susanne Moebus, Isabel Hernández, M. Ilyas Kamboh, RoseMarie Brundin, James Turton, Qiong Yang, MJ Katz, Letizia Concari, Jenny Lord, AS Beiser, C. Dirk Keene, Seppo Helisalmi, Iwona Kłoszewska, WA Kukull, AM Koivisto, Aoibhinn Lynch, Lluís Tárraga, Larson Eb, Annakaisa Haapasalo, Brian Lawlor, TH Mosley, RB Lipton, Vincenzo Solfrizzi, Michael Gill, W. T. Longstreth, TJ Montine, Vincenza Frisardi, Sara Ortega‐Cubero, Fernando Rivadeneira, RC Petersen, Vincent Deramecourt, Antonio Ciaramella, Eric Boerwinkle, Reiman Em, Nathalie Fiévet, Carlo Caltagirone, JI Rotter, JS Reisch, Olivier Hanon, Chiara Cupidi, André G. Uitterlinden, DR Royall, Carole Dufouil, Raffaele Maletta, Sonia Moreno–Grau, Mary Sano, Alexis Brice, Roberta Cecchetti, Peter St George‐Hyslop, Karen Ritchie, Magda Tsolaki, DW Tsuang, Bruno Dubois, David Craig, CK Wu, Hilkka Soininen, Despoina Avramidou, Roger L. Albin, Laura Fratiglioni, Antonia Germanou, L.G. Apostolova, Lina Keller, Maria Koutroumani, SE Arnold, Francesco Panza, Olymbia Gkatzima, Sanjay Asthana, Didier Hannequin, Patrice L. Whitehead, CS Atwood, Paolo Caffarra, Harald Hampel, CT Baldwin, Lars Lannfelt, D.C. Rubinsztein, LL Barnes, Florence Pasquier, Lutz Frölich, Sandra Barral, Bernadette McGuinness, TG Beach, J.O. Johnston, JT Becker, Peter Passmore, EH Bigio, Jonathan M. Schott, TD Bird, Jason D. Warren, BF Boeve, MK Lupton, JD Bowen, Petroula Proitsi, Adam Boxer, JF Powell, J R Burke, JK Kauwe, JM Burns, Michelangelo Mancuso, Joseph D. Buxbaum, Ubaldo Bonuccelli, NJ Cairns, Andrew McQuillin, Chuanhai Cao, Gill Livingston, CS Carlson, Nicholas Bass, CM Carlsson, John Hardy, RM Carney, José Brás, MM Carrasquillo, Rita Guerreiro, Mariet Allen, HC Chui, Elizabeth Fisher, DH Cribbs, Carlo Masullo, E.A. Crocco, Charles DeCarli, Gina Bisceglio, Malcolm Dick, Li Ma, Ranjan Duara, NR Graff-Radford, DA Evans, Angela Hodges, KM Faber, Martin Scherer, K.B. Fallon, Markus J. Riemenschneider, David W. Fardo, Reinhard Heun, MR Farlow, Steven H. Ferris, Markus Leber, TM Foroud, Isabella Heuser, Galasko Dr, Ina Giegling, Marla Gearing, M. Hüll, Geschwind Dh, J.R. Gilbert, J.C. Morris, RC Green, Kevin H. Mayo, JH Growdon, Thomas Feulner, Hamilton Rl, LE Harrell, Dmitriy Drichel, LS Honig, TD Cushion, MJ Huentelman, Paul Hollingworth, Hulette Cm, BT Hyman, Iain Marshall, GP Jarvik, Alun Meggy, Erin L. Abner, Georgina Menzies, LW Jin, Ganna Leonenko, Gyungah R Jun, Detelina Grozeva, Anna Karydas, Giancarlo Russo, JA Kaye, Young‐Jung Kim, Frank Jessen, Kowall Nw, Bruno Vellas, JH Kramer, Emma Vardy, FM LaFerla, KH Jöckel, Lah Jj, Martin Dichgans, JB Leverenz, David Mann, AI Levey, Stuart Pickering‐Brown, A.P. Lieberman, N. Klopp, Kathryn L. Lunetta, H-E Wichmann, Lyketsos Cg, Kevin Morgan, DC Marson, Kristelle Brown, Frank Martiniuk, Christopher Medway, Mash Dc, Markus M. Nöthen, Eliezer Masliah, Nigel M. Hooper, WC McCormick, Antonio Daniele, SM McCurry, Antony Bayer, AN McDavid, John Gallacher, AC McKee, Hendrik van den Bussche, M.‐Marsel Mesulam, Carol Brayne, Bruce L. Miller, Steffi G. Riedel‐Heller, C A Miller, J.H. Miller, Ammar Al‐Chalabi, Christopher E. Shaw, A Myers, Jens Wiltfang, Sid E. O’Bryant, Eliécer Coto, J.M. Olichney, Victoria Álvarez, J. E. Parisi, AB Singleton, HL Paulson, John Collinge, William Perry, Simon Mead, Elaine R. Peskind, Martin Rosser, Aimee Pierce, Natalie S. Ryan, WW Poon, Benedetta Nacmias, Huntington Potter, Sandro Sorbi, Quinn Jf, Eleonora Sacchinelli, Ashok Raj, Gianfranco Spalletta, Murray A. Raskind, Paola Bossù, Barry Reisberg, Robert Clarke, Christiane Reitz, A. David Smith, J.M. Ringman, Donald Warden, ED Roberson, Gordon Wilcock, Ekaterina Rogaeva, Ac Bruni, Rosen Hj, Maura Gallo, Rosenberg Rn, Yoav Ben‐Shlomo, MA Sager, Patrizia Mecocci, AJ Saykin, Pau Pástor, ML Cuccaro, JM Vance, JA Schneider, LS Schneider, WW Seeley, AG Smith, JA Sonnen, Salvatore Spina, RA Stern, RH Swerdlow, Tanzi Re, Trojanowski Jq, J. C. Troncoso, VM Van Deerlin, LJ Van Eldik, H.V. Vinters, J-P Vonsattel, Sandra Weıntraub, KA Welsh-Bohmer, K. C. Wilhelmsen, Jennifer Williamson, Thomas S. Wingo, RL Woltjer, C.B. Wright, CE Yu, Lei Yu, PK Crane, Bennett Da, Virginia Boccardi, PL De Jager, N Warner, OL Lopez, Stefan McDonough, Martin Ingelsson, Panos Deloukas, Carlos Cruchaga, Caroline Graff, Rhian Gwilliam, Myriam Fornage, Alison Goate, Pascual Sánchez‐Juan, PG Kehoe, Najaf Amin, Nilüfer Ertekin‐Taner, Claudine Berr, Stéphanie Debette, Shelly‐Ann Love, LJ Launer, Younkin Sg, Dartigues Jf, Chris Corcoran, MA Ikram, DW Dickson, Dominique Campion, JoAnn T. Tschanz, Helena Schmidt, Håkon Håkonarson, Ron Munger, Ryder M. Schmidt, Lindsay A. Farrer, Christine Van Broeckhoven, MC O’Donovan, AL DeStefano, Lesley Jones, Haines Jl, J.-F. Deleuze, M J Owen, Vilmundur Guðnason, Richard Mayeux, Valentina Escott‐Price, BM Psaty, Agustı́n Ruiz, Alfredo Ramı́rez, LS Wang, CM van Duijn, PA Holmans, Sudha Seshadri, Julie Williams, Philippe Amouyel, Schellenberg Gd, Jean‐Charles Lambert, MA Pericak-Vance
Bibliographic record
VenuebioRxiv (Cold Spring Harbor Laboratory) · 2018
Typepreprint
Languageen
FieldMedicine
TopicAlzheimer's disease research and treatments
Canadian institutionsOccupational Cancer Research CentreUniversity of Toronto
FundersNational Institutes of HealthBundesministerium für Bildung und ForschungEuropean CommissionDeutsche ForschungsgemeinschaftUniversity of WashingtonWellcome TrustUniversity of PennsylvaniaBrigham Young UniversityAmerican Federation for Aging ResearchMedical Research CouncilUniversität des SaarlandesAXA Research FundNational Institute on AgingAlzheimer's Association
KeywordsGenome-wide association studyGenetic associationBiologyDiseaseGeneticsDementiaGeneSingle-nucleotide polymorphismMedicineInternal medicineGenotype
Abstract
Introduction Late-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.
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 distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesMeta-epidemiology (narrow)
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.061
Threshold uncertainty score1.000
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 head0.044
GPT teacher head0.286
Teacher spread0.242 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
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
Citations42
Published2018
Admission routes1
Has abstractyes