Common, Rare and Somatic Genetic Drivers Together Double 5‑Year Atrial Fibrillation Risk: Toward an Integrated Genomic Model (IGM‑AF)

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– Whole‑genome data from 416,085 UK Biobank participants show that polygenic risk, a composite rare‑variant gene set, and somatic clonal hematopoiesis (CHIP) each independently increase 5‑year incident atrial fibrillation (AF) risk.
– Individuals carrying all three genetic drivers had at least a two‑fold higher 5‑year AF cumulative incidence versus those with a single driver.
– Integrating the integrated genomic model for AF (IGM‑AF) with a clinical risk tool (CHARGE‑AF) raised the C‑statistic to 0.80 and produced a modest net reclassification improvement (NRI 0.08), supporting additive predictive value of comprehensive genomic profiling.

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