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Cited by 19Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

A functional variant of SHARPIN confers increased risk of late-onset Alzheimer’s disease

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Asanomi, Yuya, Shigemizu, Daichi, Akiyama, Shintaro, Miyashita, Akinori, Mitsumori, Risa, Hara, Norikazu, Ikeuchi, Takeshi, Niida, Shumpei +1 more·2022·Journal of Human Genetics
DOI 10.1038/s10038-021-00987-xPMC PMC8948087
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Abstract

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN , comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls ( P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

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  • SHARPIN p.G186R (rs572750141) and p.R274W (rs77359862) have been reported to be associated with late-onset AD in the Japanese.

    “Moreover, two rare variants, p.G186R (rs572750141) and p.R274W (rs77359862), identified in the coding regions of SHARPIN, have been reported to be associated with late-onset AD in the Japanese (Table 3) [46, 47].”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [47]

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Cited by

Sorted by citations

Authors
Asanomi, Y., Shigemizu, D., Akiyama, S., Miyashita, A., Mitsumori, R., Hara, N., Ikeuchi, T., Niida, S., & Ozaki, K.
Affiliations
  • Medical Genome Center, National Center for Geriatrics and Gerontology (JP)
  • Tokyo Medical and Dental University (JP)
  • Brain Research Institute, Niigata University (JP)
  • RIKEN Center for Integrative Medical Sciences (JP)
Corresponding author
Ozaki, Kouichi
ORCID
Venue
Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-11-05
Volume
67
Issue
4
Pages
203-208
ISSN
  • 1434-5161 (ISSN-L)
  • 1435-232X
DOI
10.1038/s10038-021-00987-x
PMC
PMC8948087
OpenAlex
W3210405342
Cited by
19
References
3
Citations by year
2026: 2 · 2025: 5 · 2024: 5 · 2023: 2 · 2022: 5
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Human Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Japan Agency for Medical Research and Development (JP21dk0207045, JP21km040550, JP20dk0207028, JP21dk0207045, JP18kk0205009, JP20kk0205012, JP21dk0207045)
  • MEXT | Japan Society for the Promotion of Science (21H02470)
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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
SHARPIN, late-onset Alzheimer's disease, genetic risk variants, missense mutations, NF-κB activation, protein localization, Japanese population, mild cognitive impairment, genetic susceptibility
MeSH terms
Alzheimer Disease, Humans, Nerve Tissue Proteins, Ubiquitins, Cognitive Dysfunction

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