ArticleEBioMedicine2020
CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease.
Article in EBioMedicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- The role of genetic polymorphisms on drug response in Alzheimer's disease: a systematic review.BMC medical genomics · 2025Pooled it
- Proteomic profiling reveals structural and adhesion pathways regulated by the inverted CHRFAM7AΔ2bp variant in human neural progenitor cells.BMC neuroscience · 2026Article
- A new framework for nicotinic receptor-targeted therapeutic strategies in psychiatric and neurodegenerative disorders.Frontiers in cellular neuroscience · 2026Article
- The effect of human-specific genetic variants on neuronal spinogenesis.Frontiers in genetics · 2026Review
- CHRFAM7A diversifies human immune adaption through CaEBioMedicine · 2024Article
- Translational implications of CHRFAM7A, an elusive human-restricted fusion gene.Molecular psychiatry · 2024Review
- Serum autoantibodies against α7-nicotinic receptors in subgroups of patients with bipolar disorder or schizophrenia: clinical features and link with peripheral inflammation.Translational psychiatry · 2024Article
- Human restrictedFrontiers in neuroscience · 2024Article
- Review
- Human-specific duplicate CHRFAM7A gene is associated with more severe osteoarthritis and amplifies pain behaviours.Annals of the rheumatic diseases · 2023Article
- Review
- The Human-Restricted Isoform of the α7 nAChR, CHRFAM7A: A Double-Edged Sword in Neurological and Inflammatory Disorders.International journal of molecular sciences · 2022Review
- Deepening the understanding of CNVs on chromosome 15q11-13 by using hiPSCs: An overview.Frontiers in cell and developmental biology · 2022Review
- Alpha-7 Nicotinic Receptor Dampens Murine Osteoblastic Response to Inflammation and Age-Related Osteoarthritis.Frontiers in immunology · 2022Article
- Regulation of the acetylcholine/α7nAChR anti-inflammatory pathway in COVID-19 patients.Scientific reports · 2021Article
- Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders.International journal of molecular sciences · 2021Article
- Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions.Frontiers in molecular neuroscience · 2021Review
- iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer's Disease.International journal of molecular sciences · 2020Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundCholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models.
methodsMolecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aβ uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype.
findingsThe direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aβ neurotoxicity. Pharmacological readout translates into both first exposure (p = 0.037) and disease modifying effect (p = 0.0048) in two double blind pharmacogenetic studies.
interpretationCHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.