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

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 variants(2). Here, we compared the gene-based...

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Autores: 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; Bossu, P; Bouwman, F; Bras, J; Campion, D; Cochran, JN; Daniele, A; Dartigues, JF; Debette, S; Deleuze, JF; Denning, N; DeStefano, AL; Farrer, LA; Fernandez, 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; Lleo, 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
Tipo de documento: Artículo
Estado:Published version
Fecha de publicación:2022
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p15318
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15318
Nivel de acceso:Acceso abierto
Palabra clave:ABC transporter
ABC transporter A1
ABC transporter A7
ADAM10 endopeptidase
amyloid beta protein
amyloid precursor protein
triggering receptor expressed on myeloid cells 2
unclassified drug
ABCA1 protein, human
adenosine triphosphatase
ATP8B4 protein, human
carrier protein
low density lipoprotein receptor related protein
SORL1 protein, human
aged
Alzheimer disease
Article
atp8b4 gene
case control study
controlled study
female
gene
gene identification
genetic association
genetic variability
genome-wide association study
human
lipid metabolism
loss of function mutation
major clinical study
male
onset age
protein function
protein processing
risk assessment
risk factor
sensitivity analysis
sorl1 gene
very elderly
whole exome sequencing
genetics
Adenosine Triphosphatases
Alzheimer Disease
ATP Binding Cassette Transporter 1
Genome-Wide Association Study
Humans
LDL-Receptor Related Proteins
Membrane Transport Prote
Sumario: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 variants(2). 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-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in AD.

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