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.
Congcong Chen, Jiawen Zhu, Ziye Xu et al.· Journal of Medical Genetics· 0 citations
Background: Chronic obstructive pulmonary disease (COPD) is accompanied by systemic vascular dysfunction and microcirculatory impairment. Retinal vascular traits provide a non-invasive window into microvascular characteristics, although their shared genetic architecture with COPD remains unclear. Methods: We integrated genome-wide association study summary statistics for COPD and 17 retinal vascular traits in individuals of European ancestry. Genome-wide genetic correlations were evaluated using linkage disequilibrium score regression and high-definition likelihood. Shared pleiotropic variants were identified using pleiotropic analysis under a composite null hypothesis, followed by functional mapping and annotation, Bayesian colocalization, multi-marker analysis of genomic annotation, and functional enrichment analyses. Smoking-adjusted analyses were further conducted using genome-wide association study-by-subtraction based on genomic structural equation modeling. Results: Genetic correlation analyses identified significant associations between COPD and 10 retinal vascular traits after false discovery rate correction, with consistent directions across both methods; high-definition likelihood identified one additional trait. Positive correlations were observed for vascular bifurcation and density traits, whereas venous caliber traits showed negative correlations. Pleiotropic analysis identified 3,846 significant single-nucleotide polymorphisms across 10 trait pairs, corresponding to 2,246 unique variants and 56 unique loci. Recurrent signals were observed at 8p23.1, 15q25.1, 20q13.33, 4q31.21, and 6q24.1. Bayesian colocalization provided strong evidence for shared local genetic signals at six loci, particularly 8p23.1 and 20q13.33. Smoking-adjusted analyses showed that several genome-wide and locus-level associations remained detectable, whereas nicotinic receptor-related signals, especially at 15q25.1, were attenuated. Conclusion: COPD and retinal vascular traits show evidence of shared genetic architecture involving vascular branching, density, and venous caliber. These findings support retinal vascular traits as candidate research phenotypes for investigating systemic microvascular involvement in COPD. Further validation across diverse populations and functional studies is required.
Yu-Li Chen, Yi-Bin Li, Yijiao Tang et al.· International Journal of COP...· 0 citations
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