Holstege, Henne, Hulsman, Marc ORCID: 0000-0002-9889-3606, Charbonnier, Camille ORCID: 0000-0003-1172-0196, Grenier-Boley, Benjamin, Quenez, Olivier ORCID: 0000-0002-8273-8505, Grozeva, Detelina ORCID: 0000-0003-3239-8415, van Rooij, Jeroen G. J., Sims, Rebecca ORCID: 0000-0002-3885-1199, Ahmad, Shahzad ORCID: 0000-0002-8658-3790, Amin, Najaf, Norsworthy, Penny J., Dols-Icardo, Oriol ORCID: 0000-0003-2656-8748, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossu, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J. Nicholas, Daniele, Antonio, Dartigues, Jean-Francois, Debette, Stephanie, Deleuze, Jean-Francois, Denning, Nicola, DeStefano, Anita L., Farrer, Lindsay A., Fernandez, Maria Victoria, Fox, Nick C., Galimberti, Daniela ORCID: 0000-0002-9284-5953, Genin, Emmanuelle, Gille, Johan J. P., Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W., Lleo, Alberto, Luckcuck, Lauren, Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R., Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C., Napolioni, Valerio, Pasquier, Florence, Pastor, Pau ORCID: 0000-0002-7493-8777, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J. T., Richard, Anne-Claire, Riedel-Heller, Steffi G., Rivadeneira, Fernando, Rousseau, Stephane, Ryan, Natalie S., Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A., Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo', Tijms, Betty, Uitterlinden, Andre G., van der Lee, Sven J., Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John ORCID: 0000-0002-3122-0423, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Mead, Simon ORCID: 0000-0002-4326-1468, van der Flier, Wiesje M., van Duijn, Cornelia M., Williams, Julie, Nicolas, Gael, Bellenguez, Celine ORCID: 0000-0002-1240-7874 and Lambert, Jean-Charles . Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nature Genet.. BERLIN: NATURE PORTFOLIO. ISSN 1546-1718

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Abstract

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%(1). The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants(2). 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. Next to variants in 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. Additionally, the rare-variant burden in RIN3,CLU,ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in AD.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Holstege, HenneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hulsman, MarcUNSPECIFIEDorcid.org/0000-0002-9889-3606UNSPECIFIED
Charbonnier, CamilleUNSPECIFIEDorcid.org/0000-0003-1172-0196UNSPECIFIED
Grenier-Boley, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quenez, OlivierUNSPECIFIEDorcid.org/0000-0002-8273-8505UNSPECIFIED
Grozeva, DetelinaUNSPECIFIEDorcid.org/0000-0003-3239-8415UNSPECIFIED
van Rooij, Jeroen G. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sims, RebeccaUNSPECIFIEDorcid.org/0000-0002-3885-1199UNSPECIFIED
Ahmad, ShahzadUNSPECIFIEDorcid.org/0000-0002-8658-3790UNSPECIFIED
Amin, NajafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norsworthy, Penny J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dols-Icardo, OriolUNSPECIFIEDorcid.org/0000-0003-2656-8748UNSPECIFIED
Hummerich, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kawalia, AmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amouyel, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beecham, Gary W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berr, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bis, Joshua C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boland, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bossu, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouwman, FemkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bras, JoseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campion, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cochran, J. NicholasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daniele, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dartigues, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Debette, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denning, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeStefano, Anita L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrer, Lindsay A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez, Maria VictoriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fox, Nick C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galimberti, DanielaUNSPECIFIEDorcid.org/0000-0002-9284-5953UNSPECIFIED
Genin, EmmanuelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gille, Johan J. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Guen, YannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerreiro, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haines, Jonathan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holmes, CliveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, M. ArfanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, M. KamranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, Iris E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraaij, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lathrop, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemstra, Afina W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lleo, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luckcuck, LaurenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannens, Marcel M. A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marshall, RachelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, Eden R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masullo, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayeux, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mecocci, PatriziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meggy, AlunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mol, Merel O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, KevinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Myers, Richard M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nacmias, BenedettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naj, Adam C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Napolioni, ValerioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasquier, FlorenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pastor, PauUNSPECIFIEDorcid.org/0000-0002-7493-8777UNSPECIFIED
Pericak-Vance, Margaret A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raybould, RachelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Redon, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinders, Marcel J. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richard, Anne-ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel-Heller, Steffi G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivadeneira, FernandoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rousseau, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryan, Natalie S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saad, SalhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Juan, PascualUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schellenberg, Gerard D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheltens, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schott, Jonathan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seripa, DavideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seshadri, SudhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sie, DaoudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sistermans, Erik A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sorbi, SandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Spaendonk, ResieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spalletta, GianfrancoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tesi, Niccolo'UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tijms, BettyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uitterlinden, Andre G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Lee, Sven J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Visser, Pieter JelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wallon, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, Li-SanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zarea, AlineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clarimon, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Swieten, John C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greicius, Michael D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yokoyama, Jennifer S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruchaga, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardy, JohnUNSPECIFIEDorcid.org/0000-0002-3122-0423UNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Mead, SimonUNSPECIFIEDorcid.org/0000-0002-4326-1468UNSPECIFIED
van der Flier, Wiesje M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Williams, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicolas, GaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bellenguez, CelineUNSPECIFIEDorcid.org/0000-0002-1240-7874UNSPECIFIED
Lambert, Jean-CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699314
DOI: 10.1038/s41588-022-01208-7
Journal or Publication Title: Nature Genet.
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AMYLOID DEPOSITION; ASSOCIATION; MUTATIONS; DIAGNOSISMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69931

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