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Cited by 30Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers

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Park, Jong-Ho, Park, Inho, Youm, Emilia Moonkyung, Lee, Sejoon, Park, June-Hee, Lee, Jongan, Lee, Dong Young, Byun, Min Soo +19 more·2021·Translational Psychiatry
DOI 10.1038/s41398-021-01412-9PMC PMC8134477
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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E−07) and rs12594991 (P = 2.03E−07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.

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  • Park et al. also identified nine suggestive variants, including two SNPs located around SORCS1 that were present only in APOE ε4 carriers.

    “The authors also analyzed samples from 874 AD patients and 1063 healthy subjects, including the APOE ε4 carriers described above, and identified nine suggestive variants. These included two SNPs located around SORCS1, which were present only in ε4 carriers.”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [30]

    The Results section on the cAD chip application set reports nine AD-associated SNPs, including two intergenic SNPs between SORCS1 and LINC01435. But the same section says the association of those two SNPs with AD was observed regardless of APOE ε4 status, not only in carriers. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Park et al. identified rs1890078 located 54 kb upstream of SORCS1 and rs12594991 located in the intron of CHD2 in APOE ε4 carriers.

    “Two SNPs were identified in this analysis: rs1890078, located 54 kb upstream of SORCS1, and rs12594991, located in the intron of CHD2.”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [30]

    The Results section, “Novel variants associated with AD in APOE ε4 carriers” (page unavailable), identifies both SNPs in APOE ε4 carriers and places rs12594991 in a CHD2 intron. It describes rs1890078 as intergenic between SORCS1 and LINC01435, but does not establish that it is 54 kb upstream of SORCS1. The approximately 55 kb distance reported elsewhere in Results is between rs1890078 and a different SNP. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Park, J.-H., Park, I., Youm, E. M., Lee, S., Park, J.-H., Lee, J., Lee, D. Y., Byun, M. S., Lee, J. H., Yi, D., Chung, S. J., Park, K. W., Choi, N., Kim, S. Y., Yoon, W., An, H., Kim, K. W., Choi, S. H., Jeong, J. H., Kim, E.-J., Kang, H., Lee, J., Kim, Y., Lee, E. A., Seo, S. W., Na, D. L., & Kim, J.-W.
Affiliations
  • Samsung Medical Center (KR)
  • Seoul National University Bundang Hospital (KR)
  • Rural Development Administration (KR)
  • Seoul National University (KR)
  • Asan Medical Center (KR)
  • Inha University (KR)
  • Ewha Womans University (KR)
  • Pusan National University Hospital (KR)
  • KISTI National Supercomputing Center (KR)
  • Broad Institute (US)
Corresponding author
Kim, Jong-Won
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-05-19
Volume
11
Issue
1
Pages
296-296
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-021-01412-9
PMC
PMC8134477
OpenAlex
W3160456650
Cited by
30
References
3
Citations by year
2026: 4 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 4 · 2021: 1
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
National Research Foundation of Korea (2014M3C7A1046049, NRF2014M3C7A1046042)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, genetic risk variants, APOE ε4 carriers, SORCS1, CHD2, Korean population, novel genetic loci, rare variants
MeSH terms
Aged, Alleles, Alzheimer Disease, Apolipoproteins E, Genotype, Humans, Neurodegenerative Diseases, Apolipoprotein E4, Genome-Wide Association Study

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