Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition

Jun Pyo Kim, Sang-Hyuk Jung, Beomjin Jang, Minyoung Cho, Minku Song, Jaeyoung Kim, Beomsu Kim, Hyunwoo Lee, Daeun Shin, Eun Hye Lee, Hyemin Jang, Bo-Hyun Kim, Hongki Ham, Dokyoon Kim, Towfique Raj, Carlos Cruchaga, Hee Jin Kim, Duk L. Na, Sang Won Seo () and Hong-Hee Won ()
Additional contact information
Jun Pyo Kim: Samsung Medical Center
Sang-Hyuk Jung: University of Pennsylvania
Beomjin Jang: Sungkyunkwan University
Minyoung Cho: Sungkyunkwan University
Minku Song: Sungkyunkwan University
Jaeyoung Kim: Sungkyunkwan University
Beomsu Kim: Sungkyunkwan University
Hyunwoo Lee: Samsung Medical Center
Daeun Shin: Samsung Medical Center
Eun Hye Lee: Samsung Medical Center
Hyemin Jang: Seoul National University College of Medicine
Bo-Hyun Kim: Samsung Medical Center
Hongki Ham: Sungkyunkwan University School of Medicine
Dokyoon Kim: University of Pennsylvania
Towfique Raj: Icahn School of Medicine at Mount Sinai
Carlos Cruchaga: Washington University
Hee Jin Kim: Samsung Medical Center
Duk L. Na: Samsung Medical Center
Sang Won Seo: Samsung Medical Center
Hong-Hee Won: Sungkyunkwan University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57751-4

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