GWAS (Genome-wide association study)

A genome-wide association study (GWAS) is an agnostic scan of common single-nucleotide polymorphisms (SNPs, typically minor allele frequency >1–5%) across the genome to identify loci statistically associated with a trait or disease, using a stringent significance threshold of p<5×10⁻⁸ to control for multiple testing of ~1 million tag SNPs in linkage disequilibrium (LD) with surrounding variants. GWAS operates on the common-disease/common-variant hypothesis and is optimized for polygenic traits; most discovered variants have modest individual effect sizes (OR 1.05–1.3), requiring very large sample sizes (tens to hundreds of thousands) to detect reliably. In longevity, GWAS findings are relatively sparse: the APOE locus (particularly ε2 protection and ε4 risk) is by far the strongest and most replicated hit for exceptional longevity; other candidates including FOXO3, TOMM40/APOC1, and CDKN2B-AS1 are supported by some studies but lack universal replication. The modest GWAS yield for longevity likely reflects its heterogeneous, polygenic, and late-acting genetic architecture.