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^*

^*Autore corrispondente per questo lavoro

Amsterdam UMC
Delft University of Technology
Vrije Universiteit Amsterdam
FHU G4 Génomique
RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases
Cardiff University
Erasmus Medical Center
Leiden University
University of Oxford
CIBER - Center for Biomedical Research Network
Autonomous University of Barcelona
Medical Research Council
University of Cologne
University Montpellier
Commissariat à l’énergie atomique et aux énergies alternatives
IRCCS Fondazione Santa Lucia - Roma
Van Andel Institute
Michigan State University
CHU Hôpitaux de Bordeaux
Bordeaux Population Health Research Center
Washington University St. Louis
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
University of Milan
Université de Bretagne Occidentale
Stanford University
University of Southampton
McGill University
Columbia University
University of Perugia
University of Nottingham
IRCCS Fondazione Don Carlo Gnocchi - Milano
University of Florence
University of Camerino
Université de Lille
Hospital Universitari Mutua de Terrassa
L'Institut du Thorax
Hospital Universitario Marques de Valdecilla
Department of Hematology and Stem Cell Transplant
Blood Institute's Framingham Heart Study
Boston University
University of Texas Health Science Center at San Antonio
University of Bonn
German Center for Neurodegenerative Diseases
Reta Lila Weston Institute of Neurological Studies

Risultato della ricerca: Contributo in rivista › Articolo

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.

Lingua originale	Inglese
pagine (da-a)	1786-1794
Numero di pagine	9
Rivista	Nature Genetics
Volume	54
Numero di pubblicazione	12
DOI	https://doi.org/10.1038/s41588-022-01208-7
Stato di pubblicazione	Pubblicato - 2022

All Science Journal Classification (ASJC) codes

Genetica

Keywords

Alzheimer's disease
rare damaging variants
risk factors

Accesso al documento

10.1038/s41588-022-01208-7

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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{0d1e4bc366b949a191eaa87d434fb1de,

title = "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.",

keywords = "Alzheimer's disease, rare damaging variants, risk factors, Alzheimer's disease, rare damaging variants, risk factors",

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 Jean-Fran{\c c}ois Dartigues and St{\'e}phanie Debette and Jean-Fran{\c c}ois Deleuze 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 Anne-Claire Richard 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' 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 Li-San Wang 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 Jean-Charles Lambert",

year = "2022",

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

language = "English",

volume = "54",

pages = "1786--1794",

journal = "Nature Genetics",

issn = "1546-1718",

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, J-F, Debette, S, Deleuze, J-F, 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, A-C, 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, L-S, 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, J-C 2022, 'Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease', Nature Genetics, vol. 54, n. 12, pagg. 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

PY - 2022

Y1 - 2022

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.

KW - Alzheimer's disease

KW - rare damaging variants

KW - risk factors

KW - Alzheimer's disease

KW - rare damaging variants

KW - risk factors

UR - https://publicatt.unicatt.it/handle/10807/220025

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U2 - 10.1038/s41588-022-01208-7

DO - 10.1038/s41588-022-01208-7

M3 - Article

SN - 1546-1718

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

Abstract

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