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성균관대학교 의과대학, 삼성서울병원

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Nat. Commun., Published: 02 April 2025 | https://doi.org/10.1038/s41467-025-57751-4 Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition

Jun Pyo Kim^1,2,3,21, Sang-Hyuk Jung^4,5,6,21, Beomjin Jang^5,7,8,9,10, Minyoung Cho⁵, Minku Song⁵, Jaeyoung Kim⁵, Beomsu Kim⁵, Hyunwoo Lee^1,11, Daeun Shin^1,2,3, Eun Hye Lee^1,2,3, Hyemin Jang¹², Bo-Hyun Kim¹, Hongki Ham², Dokyoon Kim⁴, Towfique Raj^{7,8,9,10,13,14}, Carlos Cruchaga^{15,16,17,18,19}, Hee Jin Kim^1,2,3,11, Duk L. Na^1,2,3, Sang Won Seo^1,2,3,11,22 & Hong-Hee Won^5,20,22

¹Alzheimer’s Disease Convergence Research Center, Samsung Medical Center, Seoul, Republic of Korea.
²Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
³Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea.
⁴Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
⁶Department of Medical Informatics, Kangwon National University College of Medicine, Chuncheon, Republic of Korea.
⁷Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
¹²Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹³Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵Department of Psychiatry, Washington University, St. Louis, MO, USA.
¹⁶NeuroGenomics and Informatics, Washington University, St. Louis, MO, USA.
¹⁷Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA.
¹⁸Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA.
¹⁹Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
²⁰Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
²¹These authors contributed equally: Jun Pyo Kim, Sang-Hyuk Jung.
²²These authors jointly supervised this work: Sang Won Seo, Hong-Hee Won.

Corresponding authors
Correspondence to Sang Won Seo or Hong-Hee Won.

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.

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