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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

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 variants2. 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-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

SUBMITTER: Holstege H 

PROVIDER: S-EPMC9729101 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Holstege Henne H   Hulsman Marc M   Charbonnier Camille C   Grenier-Boley Benjamin B   Quenez Olivier O   Grozeva Detelina D   van Rooij Jeroen G J JGJ   Sims Rebecca R   Ahmad Shahzad S   Amin Najaf N   Norsworthy Penny J PJ   Dols-Icardo Oriol O   Hummerich Holger H   Kawalia Amit A   Amouyel Philippe P   Beecham Gary W GW   Berr Claudine C   Bis Joshua C JC   Boland Anne A   Bossù Paola P   Bouwman Femke F   Bras Jose J   Campion Dominique D   Cochran J Nicholas JN   Daniele Antonio A   Dartigues Jean-François JF   Debette Stéphanie S   Deleuze Jean-François JF   Denning Nicola N   DeStefano Anita L AL   Farrer Lindsay A LA   Fernández Maria Victoria MV   Fox Nick C NC   Galimberti Daniela D   Genin Emmanuelle E   Gille Johan J P JJP   Le Guen Yann Y   Guerreiro Rita R   Haines Jonathan L JL   Holmes Clive C   Ikram M Arfan MA   Ikram M Kamran MK   Jansen Iris E IE   Kraaij Robert R   Lathrop Marc M   Lemstra Afina W AW   Lleó Alberto A   Luckcuck Lauren L   Mannens Marcel M A M MMAM   Marshall Rachel R   Martin Eden R ER   Masullo Carlo C   Mayeux Richard R   Mecocci Patrizia P   Meggy Alun A   Mol Merel O MO   Morgan Kevin K   Myers Richard M RM   Nacmias Benedetta B   Naj Adam C AC   Napolioni Valerio V   Pasquier Florence F   Pastor Pau P   Pericak-Vance Margaret A MA   Raybould Rachel R   Redon Richard R   Reinders Marcel J T MJT   Richard Anne-Claire AC   Riedel-Heller Steffi G SG   Rivadeneira Fernando F   Rousseau Stéphane S   Ryan Natalie S NS   Saad Salha S   Sanchez-Juan Pascual P   Schellenberg Gerard D GD   Scheltens Philip P   Schott Jonathan M JM   Seripa Davide D   Seshadri Sudha S   Sie Daoud D   Sistermans Erik A EA   Sorbi Sandro S   van Spaendonk Resie R   Spalletta Gianfranco G   Tesi Niccolo' N   Tijms Betty B   Uitterlinden André G AG   van der Lee Sven J SJ   Visser Pieter Jelle PJ   Wagner Michael M   Wallon David D   Wang Li-San LS   Zarea Aline A   Clarimon Jordi J   van Swieten John C JC   Greicius Michael D MD   Yokoyama Jennifer S JS   Cruchaga Carlos C   Hardy John J   Ramirez Alfredo A   Mead Simon S   van der Flier Wiesje M WM   van Duijn Cornelia M CM   Williams Julie J   Nicolas Gaël G   Bellenguez Céline C   Lambert Jean-Charles JC  

Nature genetics 20221121 12

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%<sup>1</sup>. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants<sup>2</sup>. 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 signi  ...[more]

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