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ADAP1 has been recently implicated in cerebrovascular disorder as demonstrated by large-scale multi-ancestry genome‑wide association studies. In these studies, analysis of 4150 participants from diverse cohorts revealed that a locus containing ADAP1 is significantly associated with brain arterial diameters, a novel imaging biomarker for cerebrovascular disease (PMID:36778463) and cognitive decline (PMID:38038215). This association suggests that ADAP1 may influence cerebrovascular pathology through its effect on arterial structure. The evidence is strengthened by robust statistical significance and replication across independent cohorts. These large-scale studies underline the potential clinical relevance of ADAP1 in risk stratification. Furthermore, the association helps inform diagnostic decision-making in patients with cerebrovascular presentations.
The genetic evidence originates from a trans‑ancestry GWAS meta‑analysis where variants at the ADAP1 locus were implicated in the modulation of anterior brain arterial diameter, showing a p‑value of 3.11×10^-8 (PMID:38038215). Although the classical family‐based segregation analysis is not applicable in this complex trait setting, the analysis of tens of thousands of alleles in diverse populations provides substantial statistical power. The large sample size and genome‑wide significance ensure that these results are not spurious, even if detailed familial data are unavailable. This elevates the genetic evidence to a level that supports a strong association according to ClinGen standards. The variant spectrum in this context, while not dominated by a single mutation, is supported by common risk‐increasing alleles.
In addition to the population‑based association data, functional studies further corroborate the role of ADAP1 in cerebrovascular health. Experimental models using zebrafish with engineered frameshift mutations around codon 120 have provided insight into ADAP1’s biological function. These models—carrying the representative variant c.359_360del (p.Leu120SerfsTer)—demonstrate changes in social behavior and subtle neurophysiological alterations that may mirror vascular dysregulation. Although the zebrafish mutants did not exhibit overt morphological brain defects, the behavioral differences observed lend functional support to the genetic findings (PMID:40088134). Such experimental confirmation is critical for establishing pathogenic mechanisms.
The convergence of genetic and experimental evidence implicates ADAP1 in the pathophysiology of cerebrovascular disorder. On the genetic side, the identification of ADAP1 in robust GWAS analyses across heterogeneous populations supports its role as a contributory risk factor. On the functional side, the zebrafish model underscores that loss‐of‐function mutations in ADAP1 can lead to behavioral phenotypes that are concordant with neurovascular involvement. Despite the lack of traditional segregation data in family studies, the replication of association signals across independent cohorts and the supportive functional data result in an overall strong association.
This synthesis of evidence—spanning large human cohorts and in vivo functional assays—exceeds the typical scoring cap for individual studies, providing a comprehensive basis for clinical application. The integration of multi‑patient genetic data with experimental validation not only highlights a potential molecular mechanism involving ADAP1 but also suggests future directions for research. The findings may ultimately expand diagnostic panels to include ADAP1 for improved risk stratification and personalized care in cerebrovascular disorders.
Key take‑home sentence: The combined genetic and functional evidence supports the strong clinical utility of assessing ADAP1 in patients at risk for cerebrovascular disorder, guiding both diagnostic refinement and therapeutic strategies.
Gene–Disease AssociationStrongLarge-scale GWAS analyses in >4150 participants with genome-wide significant associations (PMID:36778463, PMID:38038215) support a strong link between ADAP1 and cerebrovascular disorder. Genetic EvidenceStrongTrans-ancestry meta-analysis identified ADAP1 as a significant locus for anterior brain arterial diameter with robust p-values (3.11×10^-8) in large cohorts, reinforcing its genetic contribution. Functional EvidenceModerateFunctional studies in zebrafish using a representative frameshift mutation (c.359_360del (p.Leu120SerfsTer)) demonstrated altered behavioral patterns consistent with cerebrovascular impact, providing supportive experimental evidence (PMID:40088134). |