Findings and insights from the genetic investigation of age of first reported occurrence for complex disorders in the UK Biobank and FinnGen

Abstract

Age of onset contains information on the timing of events relevant to disease etiology, but there has not been a systematic investigation of its heritability from GWAS data. Here, we characterize the genetic architecture of age of first occurrence and its genomic relationship with disease susceptibility for a wide range of complex disorders in the UK Biobank. For diseases with a sufficient sample size, we discover that age of first occurrence has non-trivial genetic contributions, some with specific genetic risk factors not associated with susceptibility to the disease. Through genetic correlation analysis, we show that an earlier health-event occurrence is correlated with a higher polygenic risk of disease susceptibility. An independent genetic investigation of the FinnGen cohort replicates the pattern of heritability and genetic correlation estimates. We then demonstrate that incorporating disease onset age with susceptibility may improve genetic risk prediction and stratification.