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TCF25 (HGNC:29181) has emerged as a candidate gene in the context of dementia (MONDO_0001627) through genome‑wide association studies assessing brain arterial diameters, which serve as novel biomarkers for cognitive decline and cerebrovascular disease. Two independent studies, one reported as a medRxiv preprint and another published in a peer‑reviewed journal, have implicated variants within an intronic region of TCF25 as significantly associated with alterations in brain arterial diameters (PMID:36778463) (PMID:38038215).
The genetic evidence is supported by analyses in a cohort of 4150 participants from diverse ancestries, where brain arterial diameter measurements were averaged across 13 segments and stratified by circulatory territories. In particular, two variants at a locus within TCF25 were identified in relation to the posterior brain arterial diameter, meeting stringent genome‑wide significance thresholds (P < 5 × 10^-8). This consistency in association across independent cohorts reinforces the credibility of the TCF25‑dementia link.
While a detailed list of coding variants is not available in the studies, the genetic signal is derived from non‑coding intronic variants observed by the GWAS. As such, no HGVS‐formatted coding variant (i.e. starting with “c.” and including the protein change in the “(p…)” format) can be directly reported from the available evidence. This highlights a need for further functional follow‑up to characterize the potential regulatory impact of these variants on TCF25 expression.
Functional insights into TCF25 come from a Drosophila model study where the ortholog dNulp1 was manipulated through CRISPR/Cas9‑mediated disruption. The results revealed that loss of dNulp1 impairs aspects of developmental signaling via the Wnt pathway, which may indirectly relate to neuronal and vascular functions underlying dementia. Although the phenotype studied (bent femur development) is not directly neuro‑centric, the role of Wnt signaling in both development and cellular maintenance provides mechanistic plausibility for the involvement of TCF25 in complex brain phenotypes (PMID:29437009).
Integrating the genetic and functional data, the evidence suggests that TCF25 has a moderate association with dementia. The GWAS findings in large, multi‑ethnic cohorts underscore the relevance of TCF25 variants, while the supportive experimental data, despite being derived from a non‐neuronal tissue context, contribute to our understanding of possible pathogenic mechanisms. Additional studies are warranted to further elucidate the role of regulatory variants and to extend the functional assessment in neural cell models.
Key take‑home sentence: TCF25 shows a moderate yet reproducible association with dementia risk, reinforcing its potential utility in precision diagnostics and as a target for future therapeutic investigation.
Gene–Disease AssociationModerateTwo independent GWAS studies with >4150 diverse participants identified significant intronic variants within TCF25 associated with brain arterial diameters, a biomarker linked to dementia (PMID:36778463, PMID:38038215). Genetic EvidenceModerateThe association is supported by the identification of two intronic variants in TCF25 across independent cohorts, though no HGVS‐formatted coding changes were reported. Functional EvidenceLimitedFunctional studies in a Drosophila model (dNulp1) indicate a role in Wnt signaling and developmental regulation, supporting a potential but indirect link to dementia-related pathways (PMID:29437009). |