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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 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.

Original languageEnglish
Pages (from-to)1786-1794
Number of pages9
JournalNature Genetics
Volume54
Issue number12
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
We thank all the study participants, their families, the participating medical staff, general practitioners, pharmacists and all laboratory personnel involved in patient diagnosis, blood collection, blood biobanking, DNA preparation and sequencing. The work in this manuscript was carried out on the Cartesius supercomputer, which is embedded in the Dutch national e-infrastructure with the support of the SURF Cooperative. Computing hours were granted in 2016, 2017, 2018 and 2019 to H. Holstege by the Dutch Research Council (project name: 100-plus; project nos. 15318 and 17232). This research was conducted using the funding obtained by the following study cohorts: ADES-FR, AgeCoDe-UKBonn; Barcelona SPIN; AC-EMC; ERF and Rotterdam; ADC-Amsterdam; 100-plus study; EMIF-90+; Control Brain Consortium; PERADES; StEP-AD; Knight-ADRC; UCSF/NYGC/UAB; UCL-DRC EOAD; ADSP. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). The investigators within ADNI are listed as supplementary authors and can be found in Section 5 of the Supplementary Note. Full consortium acknowledgements and funding sources are listed in Section 4 of the Supplementary Note.

Publisher Copyright:
© 2022, The Author(s).

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