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Polygenic risk prediction is a widely investigated topic because of its promising clinical applications. Genetic variants in functional regions of the genome are enriched for complex trait heritability. Here, we introduce a method for polygenic prediction, LDpred-funct, that leverages trait-specific functional priors to increase prediction accuracy. We fit priors using the recently developed baseline-LD model, including coding, conserved, regulatory, and LD-related annotations. We analytically estimate posterior mean causal effect sizes and then use cross-validation to regularize these estimates, improving prediction accuracy for sparse architectures. We applied LDpred-funct to predict 21 highly heritable traits in the UK Biobank (avg  N  = 373 K as training data). LDpred-funct attained a +4.6% relative improvement in average prediction accuracy (avg prediction  R  2  = 0.144; highest  R  2  = 0.413 for height) compared to SBayesR (the best method that does not incorporate functional information). For height, meta-analyzing training data from UK Biobank and 23andMe cohorts ( N  = 1107 K) increased prediction  R  2  to 0.431. Our results show that incorporating functional priors improves polygenic prediction accuracy, consistent with the functional architecture of complex traits.

Incorporating functional priors improves polygenic prediction accuracy in UK Biobank and 23andMe data sets