Actionable genotypes beyond the coding sequence and their association with lifespan in the UK Biobank.

BACKGROUND: The identification and reporting of actionable genotypes in the American College of Medical Genetics and Genomics (ACMG)-recommended secondary findings (SF) genes represent a key preventive strategy for hereditary diseases. Robust evidence quantifying their association with lifespan remains limited, particularly for non-coding regulatory variants, due to functional interpretation challenges. METHOD: Using data from the UK Biobank, we investigated associations between genetic variants and all-cause mortality in 490 086 participants with whole-genome sequencing. We systematically interpreted pathogenic or likely pathogenic coding variants in the 81 genes listed in the ACMG SF V.3.2. In parallel, we conducted saturation mutagenesis combined with a massively parallel reporter assay on the core promoters of these genes to generate a functional map of every potential variant, which we then used to interpret the functionally promoter variants in the cohort and evaluated their associations with mortality and disease incidence. RESULTS: Coding actionable genotypes were present in 3.40% of participants and were associated with increased all-cause mortality (HR in females, 1.42; 95% CI 1.34 to 1.52; HR in males, 1.31; 95% CI 1.24 to 1.39). All rare variants within the core promoter regions of these genes revealed no significant association with survival. Functionally promoter variants with downregulating activity of cancer genes were associated with elevated mortality risk (HR in females, 1.15; 95% CI 1.01 to 1.31; HR in males, 1.12; 95% CI 1.00 to 1.26). Furthermore, our findings provide clues that functional promoter variants may merit consideration when expanding actionable genotype lists. CONCLUSIONS: Our findings demonstrate that functionally verified promoter variants represent a previously unrecognised determinant of mortality risk, highlighting the potential value of looking beyond coding sequences in future studies.