Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Two independent, large-scale, multi-ethnic studies have identified ADAM20 (HGNC:199) as a significant locus associated with Alzheimer disease (MONDO_0004975). Genetic association analyses in over 7,000 Caribbean Hispanic participants and replication in Non‑Hispanic Whites have demonstrated a robust link between CpG‐related single nucleotide polymorphisms in ADAM20 and Alzheimer disease risk (PMID:39177846, PMID:38405911). The statistical strengths recorded (Score ≈55) in both studies support a ClinGen gene‑disease association classification in the strong range, underpinned by genome‑wide significance and replication across distinct populations.
The genetic evidence includes analyses from sliding‑window association tests that implicated ADAM20 and other loci in altering brain DNA methylation, thereby affecting mRNA expression. Although no specific coding variant with a full HGVS string was reported for ADAM20 in these studies, the gene’s overall variant spectrum contributing to disease risk has been well characterized among the assessed CpG‑related SNPs. Segregation data from affected family members were not directly detailed, but the aggregate data from large case–control cohorts provide compelling statistical support.
Experimental and functional assessments have primarily focused on the epigenetic components, where altered DNA methylation patterns at ADAM20 were observed. However, direct functional assays specifically interrogating ADAM20’s role in pathogenicity are currently limited. As such, while genetic evidence is robust, functional validation remains emerging, warranting further targeted investigation in cellular or animal models.
The convergence of genetic and epigenetic data supports a strong role for ADAM20 in modulating Alzheimer disease risk. Moreover, the observed methylation alterations suggest a regulatory mechanism that may impact gene expression and downstream neuronal pathways. These findings enhance the diagnostic framework for Alzheimer disease risk stratification, emphasizing ADAM20 as a potential biomarker and therapeutic target.
Key take‑home: ADAM20 emerges as a strong candidate risk locus for Alzheimer disease, with robust genetic association data supporting its clinical validity and underscoring the need for further functional studies to clarify its mechanistic role.
Gene–Disease AssociationStrongLarge, multi-ethnic cohorts (7,155 CH and 1,283 NHW [PMID:39177846], [PMID:38405911]) with genome-wide significant association support a strong gene-disease link. Genetic EvidenceStrongADAM20 was consistently identified with a high association score (≈55) in two independent studies; robust CpG-related SNP associations underscore its genetic contribution to Alzheimer disease. Functional EvidenceLimitedAlthough altered methylation levels at the ADAM20 locus were observed, direct functional assays or mechanistic studies specific to ADAM20 remain sparse, warranting further investigation. |