How inherited variation shapes human disease trajectories

Mendelnoulli reveals age-varying polygenic effects on 28 common diseases, improving held-out one-year discrimination (median AUC 0.95 vs 0.92) in three biobanks.

• Why it matters: Inherited variants are fixed at birth, but their health impacts shift across the life course and differ for common versus rare genetic influences.
• What they did: The longitudinal Mendelnoulli model jointly fits age-dependent polygenic and monogenic contributions to health records using 348 diseases, 36 polygenic scores, and 34 monogenic conditions across three biobanks.
• The result: For people with no prior diagnoses, it flags 8.6 more of every 100 new cases at the 5% highest risk, and for 30 established genes it selects the correct disease for 27 and ranks it first for 17.

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