Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease
The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD.
Wang Li-San、Deleuze Jean-Fran?ois、van der Lee Sven J.、Boland Anne、Guerreiro Rita、Mecocci Patrizia、Naj Adam C、Napolioni Valerio、Mol Merel O.、Raybould Rachel、Richard Anne-Claire、Myers Richard M.、Rivadeneira Fernando、Ryan Natalie S.、Holstege Henne、Hulsman Marc、Norsworthy Penny J.、Dols-Icardo Oriol、Alzheimer?ˉs Disease Neuroimaging Initiative (ADNI) database、Beecham Gary W.、Berr Claudine、Boss¨′ Paola、Bouwman Femke、Campion Dominique、Debette St¨|phanie、Haines Jonathan L.、Jansen Iris E.、Kraaij Robert、Lathrop Marc、van Spaendonk Resie、Tesi Nicc¨?lo、Tijms Betty、Martin Eden R、van Swieten John C.、Hardy John、Williams Julie、Nicolas Ga?l、Scheltens Philip、Sie Daoud、Sorbi Sandro、Denning Nicola、Schellenberg Gerard D.、Galimberti Daniela、Gille Hans、Ramirez Alfredo、Bras Jose、Nacmias Benedetta、Pastor Pau、Grozeva Detelina、Marshall Rachel、DeStefano Anita L、Lemstra Afina W.、Amin Najaf、Fernandez Maria Victoria、van Rooij Jeroen G.J.、Bellenguez C¨|line、Cochran J. Nicholas、Genin Emmanuelle、Amouyel Philippe、Greicius Michael D.、Ahmad Shahzad、Dartigues Jean-Fran?ois、Clarimon Jordi、Quenez Olivier、Daniele Antonio、Rousseau St¨|phane、Sanchez-Juan Pascual、Meggy Alun、Lambert Jean-Charles、Hummerich Holger、van Duijn Cornelia M、Farrer Lindsay A.、Pericak-Vance Margaret A.、Guen Yann Le、Cruchaga Carlos、Sistermans Erik、Mead Simon、Reinders Marcel J.T.、Mayeux Richard、Lle¨? Alberto、Luckcuck Lauren、Charbonnier Camille、Spalletta Gianfranco、Mannens Marcel M. A. M.、Uitterlinden Andr¨| G、Masullo Carlo、Redon Richard、Wagner Michael、Morgan Kevin、Seripa Davide、Seshadri Sudha、Ikram M. Kamran、Sims Rebecca、Kawalia Amit、Grenier-Boley Benjamin、Ikram M. Arfan、Bis Joshua C.、Pasquier Florence、Wallon David、Yokoyama Jennifer S.、Saad Salha、de Visser Pieter Jelle、Schott Jonathan M.、van der Flier Wiesje M.、Fox Nick C.、Riedel-Heller Steffi G、Zarea Aline、Holmes Clive
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Wang Li-San,Deleuze Jean-Fran?ois,van der Lee Sven J.,Boland Anne,Guerreiro Rita,Mecocci Patrizia,Naj Adam C,Napolioni Valerio,Mol Merel O.,Raybould Rachel,Richard Anne-Claire,Myers Richard M.,Rivadeneira Fernando,Ryan Natalie S.,Holstege Henne,Hulsman Marc,Norsworthy Penny J.,Dols-Icardo Oriol,Alzheimer?ˉs Disease Neuroimaging Initiative (ADNI) database,Beecham Gary W.,Berr Claudine,Boss¨′ Paola,Bouwman Femke,Campion Dominique,Debette St¨|phanie,Haines Jonathan L.,Jansen Iris E.,Kraaij Robert,Lathrop Marc,van Spaendonk Resie,Tesi Nicc¨?lo,Tijms Betty,Martin Eden R,van Swieten John C.,Hardy John,Williams Julie,Nicolas Ga?l,Scheltens Philip,Sie Daoud,Sorbi Sandro,Denning Nicola,Schellenberg Gerard D.,Galimberti Daniela,Gille Hans,Ramirez Alfredo,Bras Jose,Nacmias Benedetta,Pastor Pau,Grozeva Detelina,Marshall Rachel,DeStefano Anita L,Lemstra Afina W.,Amin Najaf,Fernandez Maria Victoria,van Rooij Jeroen G.J.,Bellenguez C¨|line,Cochran J. Nicholas,Genin Emmanuelle,Amouyel Philippe,Greicius Michael D.,Ahmad Shahzad,Dartigues Jean-Fran?ois,Clarimon Jordi,Quenez Olivier,Daniele Antonio,Rousseau St¨|phane,Sanchez-Juan Pascual,Meggy Alun,Lambert Jean-Charles,Hummerich Holger,van Duijn Cornelia M,Farrer Lindsay A.,Pericak-Vance Margaret A.,Guen Yann Le,Cruchaga Carlos,Sistermans Erik,Mead Simon,Reinders Marcel J.T.,Mayeux Richard,Lle¨? Alberto,Luckcuck Lauren,Charbonnier Camille,Spalletta Gianfranco,Mannens Marcel M. A. M.,Uitterlinden Andr¨| G,Masullo Carlo,Redon Richard,Wagner Michael,Morgan Kevin,Seripa Davide,Seshadri Sudha,Ikram M. Kamran,Sims Rebecca,Kawalia Amit,Grenier-Boley Benjamin,Ikram M. Arfan,Bis Joshua C.,Pasquier Florence,Wallon David,Yokoyama Jennifer S.,Saad Salha,de Visser Pieter Jelle,Schott Jonathan M.,van der Flier Wiesje M.,Fox Nick C.,Riedel-Heller Steffi G,Zarea Aline,Holmes Clive.Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease[EB/OL].(2025-03-28)[2025-06-05].https://www.medrxiv.org/content/10.1101/2020.07.22.20159251.点此复制
评论