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Cited by 21Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

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Park, Jun Young, Lee, Dongsoo, Lee, Jang Jae, Gim, Jungsoo, Gunasekaran, Tamil Iniyan, Choi, Kyu Yeong, Kang, Sarang, Do, Ah Ra +26 more·2021·Translational Psychiatry
DOI 10.1038/s41398-021-01680-5PMC PMC8595886
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Abstract

Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

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  • SHARPIN p.R274W has been associated with brain atrophy in Korean patients with AD.

    “Similarly, the p.R274W variant in SHARPIN has been associated with brain atrophy in Korean patients with AD [48].”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [48]

    The Abstract and Results report that SHARPIN rs77359862 (R274W) was associated with reduced entorhinal cortical thickness and hippocampal volume in Koreans, supporting the brain-atrophy association. The analysis included people with AD, mild cognitive impairment, and normal cognition; it does not establish the association specifically among Korean patients with AD. (LLM, conf=0.83)

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Cited by

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Authors
Park, J. Y., Lee, D., Lee, J. J., Gim, J., Gunasekaran, T. I., Choi, K. Y., Kang, S., Do, A. R., Jo, J., Park, J., Park, K., Li, D., Lee, S., Kim, H., Dhanasingh, I., Ghosh, S., Keum, S., Choi, J. H., Song, G. J., Sael, L., Rhee, S., Lovestone, S., Kim, E., Moon, S. H., Kim, B. C., Kim, S., Saykin, A. J., Nho, K., Lee, S. H., Farrer, L. A., Jun, G. R., Won, S., Lee, K. H., & Initiative, F. T. A. D. N.
Affiliations
  • Seoul National University (KR)
  • Chosun University (KR)
  • Boston University (US)
  • Chung-Ang University (KR)
  • Ajou University (KR)
  • University of Oxford (GB)
  • Samsung Medical Center (KR)
  • Chonnam National University (KR)
  • Indiana University Indianapolis (US)
Corresponding author
  • Won, Sungho
  • Lee, Kun Ho
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-11-16
Volume
11
Issue
1
Pages
590-590
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-021-01680-5
PMC
PMC8595886
OpenAlex
W3211341335
Cited by
21
References
10
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 5
FWCI
2.35
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)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
  • U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH-12, W81XWH1220012, AG024904)
  • Foundation for the National Institutes of Health (W81XWH-12-2-0012, U01AG024904, P30 AG010133, R01 AG019771, AG024904)
  • Alzheimer's Association (AG13846, U01 AG024904, P30 AG010133, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (FP6-2004-LIFESCIHEALTH-5, U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • University of Southern California (W81XWH-12-2-0012, U01 AG024904)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
  • Korea Brain Research Institute (21-BR-03-05)
  • European Commission (FP6-2004-LIFESCIHEALTH-5)
  • National Research Foundation (NRF-2014M3C7A1046041, W81XWH-12-2-0012, 21B20151213037, U01 AG024904)
  • National IT Industry Promotion Agency
  • Korea Health Industry Development Institute (HI18C0041)
  • National Research Foundation of Korea (21B20151213037, (2014M3C7A1046041, W81XWH-12-2-0012, U01 AG024904, NRF-2014M3C7A1046041)
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Ministry of Science and ICT, South Korea (1711120216)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, AG024904, AG13846)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
  • National Institute on Aging (U01-AG-024904, AG010133, P30AG010133, AG 13846, W81XWH-12-2–0012, AG 024904, R01AG048927, P30 AG010133, R01 AG019771, AG019771, U01AG032984, U01AG062602, AG032984, R01AG019771, P30AG013846, RF1AG057519, U19AG024904, P30AG072976)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • U.S. National Library of Medicine (R01LM012535)
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, SHARPIN, missense mutations, hippocampal volume, entorhinal cortex thickness, brain atrophy, amyloid-beta deposition, linear ubiquitination, HOIP, NF-κB signaling, genetic risk factors, Korean population
MeSH terms
Alzheimer Disease, Brain, Humans, Magnetic Resonance Imaging, Nerve Tissue Proteins, Ubiquitins, Amyloid beta-Peptides, Genome-Wide Association Study, Cognitive Dysfunction

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