Capturing additional genetic risk from family history for improved polygenic risk prediction
Tianyuan Lu, Vincenzo Forgetta, J. Brent Richards, Celia M.T. Greenwood
Abstract
Abstract 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.