ArticlePloS one2023
Functional characterization of a single nucleotide polymorphism associated with Alzheimer's disease in a hiPSC-based neuron model.
Article in PloS one, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 5 citations in OpenAlex.
- Protocol for combining BMP, MEK, WNT inhibition and iNGN2 to enable rapid neuronal differentiation and regional patterning from hiPSCs.STAR protocols · 2026Article
- BMP, MEK, and WNT inhibition with NGN2 expression for rapid generation of hiPSC-derived neurons amenable to regional patterning.Stem cell reports · 2025Article
- CRISPR/Cas9 and iPSC-Based Therapeutic Approaches in Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2025Review
- Co-cultures of Human-Induced Pluripotent Stem Cell-Derived Neurons, Astrocytes, and Microglia for Modeling Neurodegenerative Diseases.Methods in molecular biology (Clifton, N.J.) · 2025Article
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the FosB proto-oncogene (FOSB) and ERCC excision repair 1 (ERCC1) genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants.
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