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Large meta-analysis of genome-wide association studies expands knowledge of the genetic etiology of Alzheimer’s disease and highlights potential translational opportunities

Céline Bellenguez,Fahri Küçükali,Iris Jansen,Victor Andrade, Sonia Morenau-Grau,Najaf Amin,Benjamin Grenier-Boley,Anne Boland,Luca Kleineidam,Peter Holmans,Pablo Garcia,Rafael Campos Martin,Adam Naj,Yang Qiong,Joshua C. Bis,Vincent Damotte,Sven Van der Lee,Marcos Costa,Julien Chapuis, Vilmentas Giedraitis,María Jesús Bullido,Adolfo López de Munáin,Jordi Pérez-Tur,Pascual Sánchez-Juan,Raquel Sánchez-Valle,Victoria Álvarez,Pau Pastor,Miguel Medina,Jasper Van Dongen,Christine Van Broeckhoven,Rik Vandenberghe,Sebastiaan Engelborghs,Gael Nicolas,Florence Pasquier,Olivier Hanon,Carole Dufouil,Claudine Berr,Stéphanie Debette,Jean-François Dartigues,Gianfranco Spalletta,Benedetta Nacmias, Vincenzo Solfrezzi,Barbara Borroni,Lucio Tremolizzo,Davide Seripa,Paolo Caffarra,Antonio Daniele,Daniela Galimberti,Innocenzo Rainero,Luisa Benussi, Alesio Squassina, Patrizia Mecoci,Lucilla Parnetti,Carlo Masullo,Beatrice Arosio,John Hardy,Simon Mead,Kevin Morgan,Clive Holmes,Patrick Kehoe,Bob Woods, Eadb, Adgc,Jin Sha,Yi Zhao,Chien-Yueh Lee,Pavel P. Kuksa,Kara L. Hamilton-Nelson,Brian W. Kunkle,William S. Bush,Eden R. Martin,Li-San Wang,Richard Mayeux,Lindsay A. Farrer,Jonathan L. Haines,Margaret A. Pericak-Vance,Ruiqi Wang,Claudia Satizabal,Bruce Psaty,Oscar Lopez,Florentino Sanchez-Garcia,Børge G. Nordestgaard,Anne Tybjærg-Hansen,Jesper Qvist Thomassen,Caroline Graff,Goran Papenberg,Hilkka Soininen,Miia Kivipelto,Annakaisa Haapasalo,Tiia Ngandu,Anne Koivisto,Teemu Kuulasmaa,Laura Molina Porcel,Johannes Kornhuber,Oliver Peters,Anja schneider,Nikolaos Scarmeas,Martin Dichgans,Lutz Froelich,Dan Rujescu,Janine Diehl-Schmid,Timo Grimmer,Matthias Schmid, Markus M Möthen,Edna Grünblatt,Julius Popp,Norbert Scherbaum,Shima Mehrabian,Jürgen Deckert,Dag Aarsland,Geir Selbæk,Ingvild Saltvedt,Srdjan Djurovic,Henne Holstege,Yolande A.L. Pijnenburg,John Van Swieten,Inez Ramakers,Aad Van der Lugt,Jurgen A.H.R Claassen,Geert Jan Biessels,Philip Scheltens,Carmen Antúnez,Pablo Mir,Luis Miguel Real,Jose María García-Alberca,Gerard Piñol-Ripoll,Guillermo Garcia-Ribas,Manuel Serrano-Ríos,Julie Williams,Perminder Sachdev,Philippe Amouyel,Karen Mather,Frank Jessen,Alexandre de Mendonça,Jakub Hort,Magda Tsolaki,Ruth Frikke-Schmidt,Jordi Clarimon,Jean-François Deleuze,Sudha Seshadri,Gerald Schellenberg,Giacomina Rossi,Ole Andreassen,Martin Ingelsson,Mikko Hiltunen,Kristel Sleegers,Cornelia Van Duijn,Rebecca Sims,Wiesje M. Van der Flier,Agustin Ruiz,Alfredo Ramirez,Jean-Charles Lambert

user-5e9d449e4c775e765d44d7c9(2020)

Cited 3|Views32
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Abstract
ABSTRACT Deciphering the genetic landscape of Alzheimer’s disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer’s Disease BioBank (EADB) consortium a discovery meta-analysis of genome-wide association studies (GWAS) based on a new large case-control study and previous GWAS (in total 39,106 clinically diagnosed cases, 46,828 proxy-AD cases and 401,577 controls) with the most promising signals followed-up in independent samples (18,063 cases and 23,207 controls). In addition to 34 known AD loci, we report here the genome-wide significant association of 31 new loci with the risk of AD. Pathway-enrichment analyses strongly indicated the involvement of gene sets related to amyloid and Tau, but also highlighted microglia, in which increased gene expression corresponds to more significant AD risk. In addition, we successfully prioritized candidate genes in the majority of our new loci, with nine being primarily expressed in microglia. Finally, we observed that a polygenic risk score generated from this new genetic landscape was strongly associated with the risk of progression from mild cognitive impairment (MCI) to dementia (4,609 MCI cases of whom 1,532 converted to dementia), independently of age and the APOE e4 allele.
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Key words
Candidate gene,Genome-wide association study,Dementia,Genetic association,Disease,Allele,Genomics,Biobank,Bioinformatics,Medicine
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