Capturing additional genetic risk from family history for improved polygenic risk prediction.

Family history of complex traits may reflect transmitted rare pathogenic variants, intra-familial shared exposures to environmental and lifestyle factors, as well as a common genetic predisposition. We developed a latent factor model to quantify trait heritability in excess of that captured by a common variant-based polygenic risk score, but inferable from family history. For 941 children in the Avon Longitudinal Study of Parents and Children cohort, a joint predictor combining a polygenic risk score for height and mid-parental height was able to explain 55% of the total variance in sex-adjusted adult height z-scores, close to the estimated heritability. Marginal yet consistent risk prediction improvements were also achieved among 400,000 European ancestry participants for 11 complex diseases in the UK Biobank. Our work showcases a paradigm for risk calculation, and supports incorporation of family history into polygenic risk score-based genetic risk prediction models.