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This summary evaluates the association between NFYA (HGNC:7804) and Alzheimer disease (MONDO_0004975) as identified through whole genome sequencing (WGS) analyses from the Alzheimer’s Disease Sequencing Project. Two independent multi‐patient studies have reported significant associations, wherein a total of seventeen variants within a genomic region containing NFYA were linked to Alzheimer disease in cohorts comprising approximately 2,184 cases and 2,383 controls (PMID:37693453, PMID:38511601).
Although the statistical association is robust, there is a paucity of familial segregation data and no detailed variant‐level evidence provided. The genetic findings are drawn exclusively from association studies, limiting the interpretation of NFYA’s mechanistic role in a Mendelian sense. Nonetheless, the replication across independent cohorts supports its candidacy in the multifactorial etiology of Alzheimer disease.
The genetic evidence is based on an aggregate analysis of rare and common variants rather than a detailed phenotypic segregation or functional rescue in cellular or animal models. As a result, while the association is statistically significant this evidence does not reach the level of multi‐family segregation or extensive functional validation that would be required for a higher ClinGen classification.
From a functional standpoint, NFYA is known to play critical roles in transcriptional regulation, including the modulation of genes involved in cell cycle and apoptosis. However, functional studies directly connecting NFYA dysregulation to Alzheimer disease pathobiology are currently lacking. This limited experimental validation in an Alzheimer disease context contributes to a more cautious interpretation of its role in disease causality.
In conclusion, the evaluation of genetic and experimental data justifies a moderate level of confidence in the role of NFYA in Alzheimer disease. Additional functional studies and segregation analyses are needed to further clarify the contribution of NFYA variants to the disease process. The current evidence supports its use as a candidate gene in diagnostic decision‑making and potential commercial applications in risk stratification.
Key Take‑home: The multi‐cohort WGS studies nominate NFYA as a candidate gene for Alzheimer disease, providing a moderate level of evidence to guide further research and clinical assessment.
Gene–Disease AssociationModerateAssociation based on two independent WGS studies reporting seventeen significant variants in cohorts with 2,184 cases (PMID:37693453) and 2,184 cases (PMID:38511601); absence of familial segregation data limits the classification. Genetic EvidenceModerateSeventeen statistically significant variants detected in multi‐patient sequencing analyses implicate NFYA, although detailed variant-level resolution and segregation analysis are not provided (PMID:37693453, PMID:38511601). Functional EvidenceLimitedNFYA’s established role in transcriptional regulation is well documented, but direct experimental studies linking its function to Alzheimer disease pathogenesis are lacking. |