Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.
Paul Hollingworth,Denise Harold,Rebecca Sims,Amy Gerrish,Jean-Charles Lambert,Jean-Charles Lambert,Jean-Charles Lambert,Minerva M. Carrasquillo,Richard Abraham,Marian L. Hamshere,Jaspreet Singh Pahwa,Valentina Moskvina,Kimberley Dowzell,Nicola Jones,Alexandra Stretton,Charlene Thomas,Alexander Richards,Dobril Ivanov,Caroline S. Widdowson,Jade Chapman,Simon Lovestone,John Powell,Petroula Proitsi,Michelle K. Lupton,Carol Brayne,David C. Rubinsztein,Michael Gill,Brian A. Lawlor,Aoibhinn Lynch,Kristelle Brown,Peter Passmore,David Craig,Bernadette McGuinness,Stephen Todd,Clive Holmes,David M. A. Mann,A. David Smith,Helen Beaumont,Donald Warden,Gordon K. Wilcock,Seth Love,Patrick G. Kehoe,Nigel M. Hooper,Emma R L C Vardy,John Hardy,Simon Mead,Nick C. Fox,Martin N. Rossor,John Collinge,Wolfgang Maier,Frank Jessen,Eckart Rüther,Britta Schürmann,R. Heun,Heike Kölsch,Hendrik van den Bussche,Isabella Heuser,Johannes Kornhuber,Jens Wiltfang,Martin Dichgans,Lutz Frölich,Harald Hampel,John Gallacher,Michael Hüll,Dan Rujescu,Ina Giegling,Alison Goate,John S. K. Kauwe,Carlos Cruchaga,Petra Nowotny,John C. Morris,Kevin Mayo,Kristel Sleegers,Karolien Bettens,Sebastiaan Engelborghs,Peter Paul De Deyn,Christine Van Broeckhoven,Gill Livingston,Nicholas Bass,Hugh Gurling,Andrew McQuillin,Rhian Gwilliam,Panagiotis Deloukas,Ammar Al-Chalabi,Christopher Shaw,Magda Tsolaki,Andrew B. Singleton,Rita Guerreiro,Thomas W. Mühleisen,Markus M. Nöthen,Susanne Moebus,Karl-Heinz Jöckel,Norman Klopp,H.-Erich Wichmann,V. Shane Pankratz,Sigrid Botne Sando,Jan O. Aasly,Maria Barcikowska,Zbigniew K. Wszolek,Dennis W. Dickson,Neill R. Graff-Radford,Ronald C. Petersen,Cornelia M. van Duijn,Monique M.B. Breteler,M. Arfan Ikram,Anita L. DeStefano,Annette L. Fitzpatrick,Oscar L. Lopez,Lenore J. Launer,Sudha Seshadri,Claudine Berr,Dominique Campion,Jacques Epelbaum,Jean-François Dartigues,Christophe Tzourio,Annick Alpérovitch,Mark Lathrop,T. Feulner,Patricia Friedrich,Caterina Riehle,Michael Krawczak,Stefan Schreiber,Manuel Mayhaus,S. Nicolhaus,Stefan Wagenpfeil,Stacy Steinberg,Hreinn Stefansson,Kari Stefansson,Jon Snaedal,Sigurbjorn Bjornsson,Palmi V. Jonsson,Vincent Chouraki,Vincent Chouraki,Vincent Chouraki,Benjamin Genier-Boley,Benjamin Genier-Boley,Benjamin Genier-Boley,Mikko Hiltunen,Hilkka Soininen,Onofre Combarros,Diana Zelenika,Marc Delepine,María J. Bullido,Florence Pasquier,Ignacio Mateo,Ana Frank-García,Elisa Porcellini,Olivier Hanon,Eliecer Coto,Victoria Alvarez,Paolo Bosco,Gabriele Siciliano,Michelangelo Mancuso,Francesco Panza,Vincenzo Solfrizzi,Benedetta Nacmias,Sandro Sorbi,Paola Bossù,Paola Piccardi,Beatrice Arosio,Giorgio Annoni,Davide Seripa,Alberto Pilotto,Elio Scarpini,Daniela Galimberti,Alexis Brice,Didier Hannequin,Federico Licastro,Lesley Jones,Peter Holmans,Thorlakur Jonsson,Matthias Riemenschneider,Kevin Morgan,Steven G. Younkin,Michael John Owen,Michael Conlon O'Donovan,Philippe Amouyel,Julie Williams +177 more
TLDR
Meta-analyses of all data provided compelling evidence that ABCA7 and the MS4A gene cluster are new Alzheimer's disease susceptibility loci and independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance.Abstract:
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).read more
Citations
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Journal ArticleDOI
The amyloid hypothesis of Alzheimer's disease at 25 years
Dennis J. Selkoe,John Hardy +1 more
TL;DR: In a recent study, this article showed that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years.
Journal ArticleDOI
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
Jean-Charles Lambert,Jean-Charles Lambert,Jean-Charles Lambert,Carla A. Ibrahim-Verbaas,Denise Harold,Adam C. Naj,Rebecca Sims,Céline Bellenguez,Céline Bellenguez,Céline Bellenguez,Gyungah Jun,Anita L. DeStefano,Joshua C. Bis,Gary W. Beecham,Benjamin Grenier-Boley,Benjamin Grenier-Boley,Benjamin Grenier-Boley,Giancarlo Russo,Tricia A. Thornton-Wells,Nicola Jones,Albert V. Smith,Vincent Chouraki,Vincent Chouraki,Vincent Chouraki,Charlene Thomas,M. Arfan Ikram,Diana Zelenika,Badri N. Vardarajan,Yoichiro Kamatani,Chiao-Feng Lin,Amy Gerrish,Helena Schmidt,Brian W. Kunkle,Melanie L. Dunstan,Agustín Ruiz,Marie-Thérèse Bihoreau,Seung Hoan Choi,Christiane Reitz,Florence Pasquier,Paul Hollingworth,Alfredo Ramirez,Olivier Hanon,Annette L. Fitzpatrick,Joseph D. Buxbaum,Dominique Campion,Paul K. Crane,Clinton T. Baldwin,Tim Becker,Tim Becker,Vilmundur Gudnason,Carlos Cruchaga,David Craig,Najaf Amin,Claudine Berr,Oscar L. Lopez,Philip L. De Jager,Philip L. De Jager,Vincent Deramecourt,Janet A. Johnston,Denis A. Evans,Simon Lovestone,Luc Letenneur,Francisco J. Morón,David C. Rubinsztein,Gudny Eiriksdottir,Kristel Sleegers,Kristel Sleegers,Alison Goate,Nathalie Fievet,Nathalie Fievet,Matthew J. Huentelman,Michael Gill,Kristelle Brown,M. Ilyas Kamboh,Lina Keller,Pascale Barberger-Gateau,Bernadette McGuinness,Eric B. Larson,Eric B. Larson,Robert C. Green,Amanda J. Myers,Carole Dufouil,Stephen Todd,David Wallon,Seth Love,Ekaterina Rogaeva,John Gallacher,Peter St George-Hyslop,Peter St George-Hyslop,Jordi Clarimón,Alberto Lleó,Anthony Bayer,Debby W. Tsuang,Lei Yu,Magda Tsolaki,Paola Bossù,Gianfranco Spalletta,Petroula Proitsi,John Collinge,Sandro Sorbi,Florentino Sanchez-Garcia,Nick C. Fox,John Hardy,Maria Candida Deniz Naranjo,Paolo Bosco,Robert Clarke,Carol Brayne,Daniela Galimberti,Michelangelo Mancuso,Fiona E. Matthews,Genetic,Environmental Risk in Alzheimer's Disease,Environmental Risk in Alzheimer's Disease,Cohorts for Heart,Cohorts for Heart,Susanne Moebus,Patrizia Mecocci,Maria Del Zompo,Wolfgang Maier,Wolfgang Maier,Harald Hampel,Harald Hampel,Alberto Pilotto,María J. Bullido,María J. Bullido,Francesco Panza,Paolo Caffarra,Paolo Caffarra,Benedetta Nacmias,John R. Gilbert,Manuel Mayhaus,Lars Lannfelt,Hakon Hakonarson,Sabrina Pichler,Minerva M. Carrasquillo,Martin Ingelsson,Duane Beekly,Victoria Alvarez,Fanggeng Zou,Otto Valladares,Steven G. Younkin,Eliecer Coto,Kara L. Hamilton-Nelson,Wei Gu,Cristina Razquin,Pau Pastor,Ignacio Mateo,Michael John Owen,Kelley Faber,Palmi V. Jonsson,Onofre Combarros,Michael Conlon O'Donovan,Laura B. Cantwell,Hilkka Soininen,Deborah Blacker,Simon Mead,Thomas H. Mosley,David A. Bennett,Tamara B. Harris,Laura Fratiglioni,Laura Fratiglioni,Clive Holmes,Renée F.A.G. de Bruijn,Peter Passmore,Thomas J. Montine,Karolien Bettens,Karolien Bettens,Jerome I. Rotter,Alexis Brice,Alexis Brice,Kevin Morgan,Tatiana Foroud,Walter A. Kukull,Didier Hannequin,John Powell,Mike A. Nalls,Karen Ritchie,Kathryn L. Lunetta,John S. K. Kauwe,Eric Boerwinkle,Eric Boerwinkle,Matthias Riemenschneider,Mercè Boada,Mikko Hiltunen,Eden R. Martin,Reinhold Schmidt,Dan Rujescu,Li-San Wang,Jean-François Dartigues,Jean-François Dartigues,Richard Mayeux,Christophe Tzourio,Albert Hofman,Markus M. Nöthen,Caroline Graff,Caroline Graff,Bruce M. Psaty,Bruce M. Psaty,Lesley Jones,Jonathan L. Haines,Peter Holmans,Mark Lathrop,Mark Lathrop,Margaret A. Pericak-Vance,Lenore J. Launer,Lindsay A. Farrer,Cornelia M. van Duijn,Christine Van Broeckhoven,Christine Van Broeckhoven,Valentina Moskvina,Sudha Seshadri,Julie Williams,Gerard D. Schellenberg,Philippe Amouyel,Philippe Amouyel,Philippe Amouyel +215 more
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Journal ArticleDOI
TREM2 Variants in Alzheimer's Disease
Rita Guerreiro,Rita Guerreiro,Aleksandra Wojtas,Jose Bras,Minerva M. Carrasquillo,Ekaterina Rogaeva,Elisa Majounie,Carlos Cruchaga,Celeste Sassi,Celeste Sassi,John S. K. Kauwe,Steven G. Younkin,Lili-Naz Hazrati,John Collinge,Jennifer M. Pocock,Tammaryn Lashley,Julie Williams,Jean-Charles Lambert,Philippe Amouyel,Alison Goate,Rosa Rademakers,Kevin Morgan,John Powell,Peter St George-Hyslop,Peter St George-Hyslop,Andrew B. Singleton,John Hardy +26 more
TL;DR: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.
Journal ArticleDOI
Host microbiota constantly control maturation and function of microglia in the CNS
Daniel Erny,Anna Lena Hrabě de Angelis,Diego Jaitin,Peter Wieghofer,Ori Staszewski,Eyal David,Hadas Keren-Shaul,Tanel Mahlakõiv,Kristin Jakobshagen,Thorsten Buch,Vera Schwierzeck,Olaf Utermöhlen,Eunyoung Chun,Wendy S. Garrett,Kathy D. McCoy,Andreas Diefenbach,Peter Staeheli,Bärbel Stecher,Ido Amit,Marco Prinz +19 more
TL;DR: It is determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis and mice deficient for the SCFA receptor FFAR2 mirroredmicroglia defects found under GF conditions, suggesting that host bacteria vitally regulate microglian maturation and function.
Journal ArticleDOI
Variant of TREM2 associated with the risk of Alzheimer's disease
Thorlakur Jonsson,Hreinn Stefansson,Stacy Steinberg,Ingileif Jonsdottir,Palmi V. Jonsson,Jon Snaedal,Sigurbjorn Bjornsson,Johanna Huttenlocher,Allan I. Levey,James J. Lah,Dan Rujescu,Harald Hampel,Ina Giegling,Ole A. Andreassen,Knut Engedal,Ingun Ulstein,Srdjan Djurovic,Carla A. Ibrahim-Verbaas,Albert Hofman,M. Arfan Ikram,Cornelia M. van Duijn,Unnur Thorsteinsdottir,Augustine Kong,Kari Stefansson +23 more
TL;DR: These findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease and find that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers.
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