Transethnic analysis identifies <i>SORL1</i> variants and haplotypes protective against Alzheimer's disease
We examined the AD-protective mechanisms of SORL1 in the general population across diverse ancestral backgrounds by jointly analyzing data from three East Asian cohorts (ie, mainland China, Hong Kong, and Japan) and a European cohort. Comparative analysis unveiled key ethnic-specific SORL1 genetic variants and haplotypes. Among these, the SORL1 minor haplotype, Hap_A, emerged as the primary AD-protective factor in East Asians. Hap_A exerts significant AD-protective effects in both APOE ε4 carriers and non-carriers. SORL1 haplotype Hap_A is associated with cognitive function, brain volume, and the activity of specific neuronal and immune-related pathways closely connected to AD risk. Protective variants within Hap_A are linked to increased SORL1 expression in human tissues. We identified an isoform-specific missense variant in Hap_A that modifies the function and levels of a truncated SORL1 protein isoform that is poorly investigated.
Authors
- Norikazu Hara (ORCID: https://orcid.org/0000-0001-8525-3469)
- Ronnie M.N. Lo
- John Hardy (ORCID: https://orcid.org/0000-0002-3122-0423)
- Vincent Mok (ORCID: https://orcid.org/0000-0002-8102-8835)
- Xiaopu Zhou (ORCID: https://orcid.org/0000-0001-5307-5805)
- Fanny C.F. Ip (ORCID: https://orcid.org/0000-0001-5162-1761)
- Nancy Y. Ip (ORCID: https://orcid.org/0000-0002-2763-8907)
- Han Cao (ORCID: https://orcid.org/0000-0003-3612-6169)
- Takeshi Ikeuchi
- Amy K.Y. Fu (ORCID: https://orcid.org/0000-0003-4085-6201)
- Yuewen Chen (ORCID: https://orcid.org/0000-0002-7876-2174)
- Yuanbing Jiang (ORCID: https://orcid.org/0000-0001-8585-0714)
- Timothy Kwok (ORCID: https://orcid.org/0000-0001-9253-3549)
- Kin Ying Mok (ORCID: https://orcid.org/0000-0003-3145-880X)
- Akinori Miyashita (ORCID: https://orcid.org/0000-0003-2508-9649)
- Yu Chen (ORCID: https://orcid.org/0000-0002-7569-9472)
- Huan Zhong (ORCID: https://orcid.org/0000-0002-7294-2254)
- Wing Yu Fu
- Bonnie Wing Yan Wong
- Elaine Yee Ling Cheng
Institutions
- Chinese University of Hong Kong (HK)
- Hong Kong University of Science and Technology (HK)
- HKUST Shenzhen Research Institute (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Nano and Advanced Materials Institute (CN)
- University College London (GB)
- Niigata University (JP)
- University of Hong Kong (HK)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2024-12-10
- DOI
- https://doi.org/10.1002/alz.14214
- Citations
- 9
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.94
Funders
- Eli Lilly and Company
- University of Southern California
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- National Natural Science Foundation of China
- University Grants Committee
- Innovation and Technology Commission
- Eisai
- Hong Kong University of Science and Technology
- Shenzhen Virtual University Park
- Shenzhen Fundamental Research Program
- Japan Society for the Promotion of Science