Nature genetics · 2022

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

СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен

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Holstege Henne, Hulsman Marc, Charbonnier Camille, Grenier-Boley Benjamin, Quenez Olivier, Grozeva Detelina, van Rooij Jeroen G J, Sims Rebecca, Ahmad Shahzad, Amin Najaf, Norsworthy Penny J, Dols-Icardo Oriol, Hummerich Holger, Kawalia Amit, Amouyel Philippe, Beecham Gary W, Berr Claudine, Bis Joshua C, Boland Anne, Bossù Paola, Bouwman Femke, Bras Jose, Campion Dominique, Cochran J Nicholas, Daniele Antonio, Dartigues Jean-François, Debette Stéphanie, Deleuze Jean-François, Denning Nicola, DeStefano Anita L, Farrer Lindsay A, Fernández Maria Victoria, Fox Nick C, Galimberti Daniela, 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, Lleó 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, Pericak-Vance Margaret A, Raybould Rachel, Redon Richard, Reinders Marcel J T, Richard Anne-Claire, Riedel-Heller Steffi G, Rivadeneira Fernando, Rousseau Stéphane, 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 André 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, Ramirez Alfredo, Mead Simon, van der Flier Wiesje M, van Duijn Cornelia M, Williams Julie, Nicolas Gaël, Bellenguez Céline, Lambert Jean-Charles

Аннотация

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.

Предметные рубрики MeSH

Humans Adenosine Triphosphatases Alzheimer Disease ATP Binding Cassette Transporter 1 Genome-Wide Association Study Risk Factors Exosomes LDL-Receptor Related Proteins Membrane Transport Proteins

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH