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Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition
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Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition
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Journal Article
Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition
2025
Overview
GWAS of Alzheimer’s disease have been predominantly based on European ancestry cohorts with clinically diagnosed patients. Increasing the ancestral diversity of GWAS and focusing on imaging brain biomarkers for Alzheimer’s disease may lead to the identification of new genetic loci. Here, we perform a GWAS on cerebral β-amyloid deposition measured by PET imaging in 3,885 East Asians and a cross-ancestry GWAS meta-analysis with data from 11,816 European participants. Our GWAS analysis replicates known loci (
APOE4
,
CR1
, and
FERMT2
) and identifies a novel locus near
SORL1
that is significantly associated with β-amyloid deposition. Single-nucleus expression analysis shows that
SORL1
is differentially expressed according to β-amyloid positivity in microglia. Our joint association analysis using the
SORL1
lead variant (rs76490923) and the
APOE4
allele demonstrates that the risk of β-amyloid deposition is reduced by up to 43.5% in
APOE4
non-carriers and up to 55.6% in
APOE4
carriers, according to the allelic dosage of the rs76490923 T allele. Our findings suggest that
SORL1
may play an important role in the pathogenesis of Alzheimer’s disease, particularly in relation to β-amyloid deposition.
A cross-ancestry GWAS meta-analysis of β-amyloid deposition in East Asian and European populations identifies a novel
SORL1
locus and highlights its differential expression in microglia associated with β-amyloid positivity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/43
/ 49/91
/ 59/78
/ Aged
/ Alleles
/ Alzheimer Disease - diagnostic imaging
/ Alzheimer Disease - genetics
/ Alzheimer Disease - metabolism
/ Amyloid beta-Peptides - metabolism
/ Apolipoprotein E4 - genetics
/ East Asian People - genetics
/ Eastern European People - genetics
/ Female
/ Genetic Predisposition to Disease
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Humanities and Social Sciences
/ Humans
/ LDL-Receptor Related Proteins - genetics
/ LDL-Receptor Related Proteins - metabolism
/ Male
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Polymorphism, Single Nucleotide
/ Positron emission tomography
/ Science
