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

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TitleExome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2022
AuthorsHolstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JGJ, Sims R, Ahmad S, Amin N et al.
JournalNat Genet
Volume54
Issue12
Pagination1786-1794
Date Published12/2022
ISSN1546-1718
KeywordsAdenosine Triphosphatases, Alzheimer Disease, ATP Binding Cassette Transporter 1, Exosomes, Genome-Wide Association Study, Humans, Risk Factors
Abstract

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants. 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.
DOI10.1038/s41588-022-01208-7
Alternate JournalNat Genet
PubMed ID36411364
PubMed Central IDPMC9729101
Grant ListU24 AG021886 / AG / NIA NIH HHS / United States
MC_UU_00024/1 / MRC_ / Medical Research Council / United Kingdom
U24 AG056270 / AG / NIA NIH HHS / United States
G0701075 / MRC_ / Medical Research Council / United Kingdom
G0901254 / MRC_ / Medical Research Council / United Kingdom
R00 AG068271 / AG / NIA NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
MR/N026004/1 / MRC_ / Medical Research Council / United Kingdom