Kim Jun Pyo, Jung Sang-Hyuk, Jang Beomjin, Cho Minyoung, Song Minku, Kim Jaeyoung, Kim Beomsu, Lee Hyunwoo, Shin Daeun, Lee Eun Hye, Jang Hyemin, Kim Bo-Hyun, Ham Hongki, Kim Dokyoon, Raj Towfique, Cruchaga Carlos, Kim Hee Jin, Na Duk L, Seo Sang Won, Won Hong-Hee
Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, Republic of Korea.
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Nat Commun. 2025 Apr 2;16(1):3150. doi: 10.1038/s41467-025-57751-4.
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.
阿尔茨海默病的全基因组关联研究（GWAS）主要基于欧洲血统队列中的临床诊断患者。增加GWAS的祖先多样性并聚焦于阿尔茨海默病的脑成像生物标志物，可能会发现新的基因位点。在此，我们对3885名东亚人通过PET成像测量的脑β-淀粉样蛋白沉积进行了GWAS，并与来自11816名欧洲参与者的数据进行了跨祖先GWAS荟萃分析。我们的GWAS分析重复验证了已知位点（APOE4、CR1和FERMT2），并在SORL1附近鉴定出一个与β-淀粉样蛋白沉积显著相关的新位点。单核表达分析表明，SORL1在小胶质细胞中根据β-淀粉样蛋白阳性情况存在差异表达。我们使用SORL1主要变体（rs76490923）和APOE4等位基因进行的联合关联分析表明，根据rs76490923 T等位基因的等位基因剂量，APOE4非携带者中β-淀粉样蛋白沉积的风险降低了43.5%，APOE4携带者中降低了55.6%。我们的研究结果表明，SORL1可能在阿尔茨海默病的发病机制中起重要作用，特别是与β-淀粉样蛋白沉积有关。
