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 Bossù; Femke 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

doi:10.1038/s41588-022-01208-7

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 Bossù

Femke 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

Vrije Universiteit Amsterdam
Amsterdam UMC
Delft University of Technology
Université de Rouen Normandie
Université de Lille
Cardiff University School of Medicine
Medical Research Council
Autonomous University of Barcelona
Instituto de Salud Carlos III
University Hospital Cologne
Leonard M. Miller School of Medicine
Université de Montpellier
University of Washington School of Medicine
Université Paris-Saclay
IRCCS Fondazione Santa Lucia - Roma
Van Andel Institute
Michigan State University
HudsonAlpha Institute for Biotechnology
Agostino Gemelli University Hospital Foundation IRCCS
Bordeaux Population Health  Centre de Recherche U1219
University Hospital of Bordeaux
Boston University School of Public Health
The Framingham Heart Study
Boston University School of Medicine
Boston University
Washington University School of Medicine in St. Louis
University College London
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
University of Milan
Université de Bretagne Occidentale
Stanford University
Case Western Reserve University School of Medicine
University of Southampton
McGill University
University of Amsterdam
Catholic University of the Sacred Heart
Columbia University
University of Perugia
University of Nottingham
University of Florence
IRCCS Fondazione Don Carlo Gnocchi - Milano
UPenn School of Medicine
University of Camerino
Hospital Universitari Mútua Terrassa
University of Barcelona
L'Institut du Thorax Curie-Montsouris
Leipzig University
Hospital Universitario Marques de Valdecilla
Laboratory for Advanced Hematological Diagnostics
Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases
University Hospital Bonn
German Center for Neurodegenerative Diseases
University of California at San Francisco
University of Cologne
Leiden Academic Centre for Drug Research (LACDR)
University of Oxford

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	1786-1794
Number of pages	9
Journal	Nature Genetics
Volume	54
Issue number	12
DOIs	https://doi.org/10.1038/s41588-022-01208-7
Publication status	Published - 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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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s diseaseFinal published version, 7.94 MBLicence: CC BY

Cite this

Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., van Rooij, J. G. J., Sims, R., Ahmad, S., Amin, N., Norsworthy, P. J., Dols-Icardo, O., Hummerich, H., Kawalia, A., Amouyel, P., Beecham, G. W., Berr, C., Bis, J. C., Boland, A., ... Lambert, J. C. (2022). Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nature Genetics, 54(12), 1786-1794. https://doi.org/10.1038/s41588-022-01208-7

@article{0f39bae535a646a1a1dfcb84ae9afde3,

title = "Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer{\textquoteright}s disease",

abstract = "Alzheimer{\textquoteright}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{\textemdash}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.",

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

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{\textquoteright}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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41588-022-01208-7",

language = "English",

volume = "54",

pages = "1786--1794",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

Holstege, H, Hulsman, M, Charbonnier, C, Grenier-Boley, B, Quenez, O, Grozeva, D, van Rooij, JGJ, Sims, R, Ahmad, S, Amin, N, Norsworthy, PJ, Dols-Icardo, O, Hummerich, H, Kawalia, A, Amouyel, P, Beecham, GW, Berr, C, Bis, JC, Boland, A, Bossù, P, Bouwman, F, Bras, J, Campion, D, Cochran, JN, Daniele, A, Dartigues, JF, Debette, S, Deleuze, JF, Denning, N, DeStefano, AL, Farrer, LA, Fernández, MV, Fox, NC, Galimberti, D, Genin, E, Gille, JJP, Le Guen, Y, Guerreiro, R, Haines, JL, Holmes, C, Ikram, MA , Ikram, MK, Jansen, IE, Kraaij, R, Lathrop, M, Lemstra, AW, Lleó, A, Luckcuck, L, Mannens, MMAM, Marshall, R, Martin, ER, Masullo, C, Mayeux, R, Mecocci, P, Meggy, A, Mol, MO, Morgan, K, Myers, RM, Nacmias, B, Naj, AC, Napolioni, V, Pasquier, F, Pastor, P, Pericak-Vance, MA, Raybould, R, Redon, R, Reinders, MJT, Richard, AC, Riedel-Heller, SG, Rivadeneira, F, Rousseau, S, Ryan, NS, Saad, S, Sanchez-Juan, P, Schellenberg, GD, Scheltens, P, Schott, JM, Seripa, D, Seshadri, S, Sie, D, Sistermans, EA, Sorbi, S, van Spaendonk, R, Spalletta, G, Tesi, N, Tijms, B, Uitterlinden, AG, van der Lee, SJ, Visser, PJ, Wagner, M, Wallon, D, Wang, LS, Zarea, A, Clarimon, J, van Swieten, JC, Greicius, MD, Yokoyama, JS, Cruchaga, C, Hardy, J, Ramirez, A, Mead, S, van der Flier, WM, van Duijn, CM, Williams, J, Nicolas, G, Bellenguez, C & Lambert, JC 2022, 'Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease', Nature Genetics, vol. 54, no. 12, pp. 1786-1794. https://doi.org/10.1038/s41588-022-01208-7

TY - JOUR

T1 - Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

AU - Holstege, Henne

AU - Hulsman, Marc

AU - Charbonnier, Camille

AU - Grenier-Boley, Benjamin

AU - Quenez, Olivier

AU - Grozeva, Detelina

AU - van Rooij, Jeroen G.J.

AU - Sims, Rebecca

AU - Ahmad, Shahzad

AU - Amin, Najaf

AU - Norsworthy, Penny J.

AU - Dols-Icardo, Oriol

AU - Hummerich, Holger

AU - Kawalia, Amit

AU - Amouyel, Philippe

AU - Beecham, Gary W.

AU - Berr, Claudine

AU - Bis, Joshua C.

AU - Boland, Anne

AU - Bossù, Paola

AU - Bouwman, Femke

AU - Bras, Jose

AU - Campion, Dominique

AU - Cochran, J. Nicholas

AU - Daniele, Antonio

AU - Dartigues, Jean François

AU - Debette, Stéphanie

AU - Deleuze, Jean François

AU - Denning, Nicola

AU - DeStefano, Anita L.

AU - Farrer, Lindsay A.

AU - Fernández, Maria Victoria

AU - Fox, Nick C.

AU - Galimberti, Daniela

AU - Genin, Emmanuelle

AU - Gille, Johan J.P.

AU - Le Guen, Yann

AU - Guerreiro, Rita

AU - Haines, Jonathan L.

AU - Holmes, Clive

AU - Ikram, M. Arfan

AU - Ikram, M. Kamran

AU - Jansen, Iris E.

AU - Kraaij, Robert

AU - Lathrop, Marc

AU - Lemstra, Afina W.

AU - Lleó, Alberto

AU - Luckcuck, Lauren

AU - Mannens, Marcel M.A.M.

AU - Marshall, Rachel

AU - Martin, Eden R.

AU - Masullo, Carlo

AU - Mayeux, Richard

AU - Mecocci, Patrizia

AU - Meggy, Alun

AU - Mol, Merel O.

AU - Morgan, Kevin

AU - Myers, Richard M.

AU - Nacmias, Benedetta

AU - Naj, Adam C.

AU - Napolioni, Valerio

AU - Pasquier, Florence

AU - Pastor, Pau

AU - Pericak-Vance, Margaret A.

AU - Raybould, Rachel

AU - Redon, Richard

AU - Reinders, Marcel J.T.

AU - Richard, Anne Claire

AU - Riedel-Heller, Steffi G.

AU - Rivadeneira, Fernando

AU - Rousseau, Stéphane

AU - Ryan, Natalie S.

AU - Saad, Salha

AU - Sanchez-Juan, Pascual

AU - Schellenberg, Gerard D.

AU - Scheltens, Philip

AU - Schott, Jonathan M.

AU - Seripa, Davide

AU - Seshadri, Sudha

AU - Sie, Daoud

AU - Sistermans, Erik A.

AU - Sorbi, Sandro

AU - van Spaendonk, Resie

AU - Spalletta, Gianfranco

AU - Tesi, Niccolo’

AU - Tijms, Betty

AU - Uitterlinden, André G.

AU - van der Lee, Sven J.

AU - Visser, Pieter Jelle

AU - Wagner, Michael

AU - Wallon, David

AU - Wang, Li San

AU - Zarea, Aline

AU - Clarimon, Jordi

AU - van Swieten, John C.

AU - Greicius, Michael D.

AU - Yokoyama, Jennifer S.

AU - Cruchaga, Carlos

AU - Hardy, John

AU - Ramirez, Alfredo

AU - Mead, Simon

AU - van der Flier, Wiesje M.

AU - van Duijn, Cornelia M.

AU - Williams, Julie

AU - Nicolas, Gaël

AU - Bellenguez, Céline

AU - Lambert, Jean Charles

N1 - 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).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85142346472

U2 - 10.1038/s41588-022-01208-7

DO - 10.1038/s41588-022-01208-7

M3 - Article

C2 - 36411364

AN - SCOPUS:85142346472

SN - 1061-4036

VL - 54

SP - 1786

EP - 1794

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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