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

Area of Science:

• Genetics and genomics
• Preventive medicine
• Molecular biology

Background:

• Actionable genotypes in American College of Medical Genetics and Genomics (ACMG)-recommended secondary findings (SF) genes are crucial for hereditary disease prevention.
• Limited data exists on the association between genetic variants, especially non-coding regulatory ones, and lifespan due to interpretation challenges.

Purpose of the Study:

• To investigate the association between genetic variants in ACMG SF genes and all-cause mortality using UK Biobank data.
• To functionally interpret promoter variants and assess their impact on mortality and disease incidence.

Main Methods:

• Whole-genome sequencing data from 490,086 UK Biobank participants.
• Systematic interpretation of pathogenic/likely pathogenic coding variants in 81 ACMG SF genes.
• Saturation mutagenesis and reporter assays to functionally map core promoter variants and assess their association with mortality.

Main Results:

• Coding actionable genotypes (3.40% of participants) were linked to increased all-cause mortality in both sexes.
• Rare variants in core promoter regions showed no significant survival association.
• Functionally verified promoter variants with gene-downregulating activity correlated with elevated mortality risk.

Conclusions:

• Functionally verified promoter variants are significant, previously unrecognized determinants of mortality risk.
• Future studies should consider non-coding functional variants beyond coding sequences for a comprehensive understanding of disease risk and lifespan.