ArticleMolecular medicine (Cambridge, Mass.)2019
A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease.
Article in Molecular medicine (Cambridge, Mass.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 3 of them syntheses that pooled it.
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Who cites it
30 citing papers in PubMed, 3 syntheses or guidelines pooled it, 44 citations in OpenAlex.
- A reappraisal of APOE genetic effects on Alzheimer's disease risk in the Japanese population: a meta-analysis.Molecular neurodegeneration · 2026Pooled it
- Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer's disease risk.Translational psychiatry · 2021Pooled it
- Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target.Nature reviews. Drug discovery · 2020Pooled it
- NF-κB across the Alzheimer disease spectrum: Context-dependent protective and pathogenic roles.IBRO neuroscience reports · 2026Review
- APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.Nature genetics · 2026Article
- RIPK 1 in Alzheimer's Disease: Research Progress Integrating Pathogenesis on Necroptosis-Related Neuroinflammation, and Potential Therapeutic Strategies.Biomedicines · 2026Review
- Evaluation of plasma p-tau217 biomarkers in detecting amyloid pathology and predicting cognitive outcomes: Observations from Japanese Alzheimer's disease neuroimaging initiative cohort.The journal of prevention of Alzheimer's disease · 2026Article
- Association of rareJournal of Alzheimer's disease : JAD · 2025Article
- Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer's disease and a cumulative effects model for risk liability.Nature communications · 2025Article
- The impact of rare genetic variants on Alzheimer disease.Nature reviews. Neurology · 2025Review
- Shared interactions of six neurotropic viruses with 38 human proteins: a computational and literature-based exploration of viral interactions and hijacking of human proteins in neuropsychiatric disorders.Discover mental health · 2025Article
- Whole-genome sequencing study in Koreans identifies novel loci for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- CRISPR/Cas9-mediated knock-in cells of the late-onset Alzheimer's disease-risk variant, SHARPIN G186R, reveal reduced NF-κB pathway and accelerated Aβ secretion.Journal of human genetics · 2024Article
- Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease.Research square · 2023Article
- Alzheimer's Disease: An Updated Overview of Its Genetics.International journal of molecular sciences · 2023Review
- The neuroimmune axis of Alzheimer's disease.Genome medicine · 2023Review
- Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer's disease and amyotrophic lateral sclerosis.Frontiers in molecular biosciences · 2023Review
- Intervention of next-generation sequencing in diagnosis of Alzheimer's disease: challenges and future prospects.Dementia & neuropsychologia · 2023Review
- Necroptosis: A Pathogenic Negotiator in Human Diseases.International journal of molecular sciences · 2022Review
- SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer's Disease?Cellular and molecular neurobiology · 2022Review
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLate-onset Alzheimer's disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population.
methodsTo identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk.
resultsVia step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10
conclusionsOur work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development.
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