> Polygenic scores are touted as this magic bullet for understanding the contribution of genetics to a phenotype but are utterly imperfect models for what actua

> Polygenic scores are touted as this magic bullet for understanding the contribution of genetics to a phenotype but are utterly imperfect models for what actually occurs due to pleiotropy and epigenetics Agreed! To be a bit more charitable to polygenic scores, they can be mediocre descriptive models—given a real individual’s genotype, they can sometimes decently predict their phenotype (if you consider explaining ~10% of phenotypic variance “decent”). They are unequivocally horrible generative models—you will not obtain a synthetic genotype that would result in a desired phenotype by sampling from a PGS model, i.e. by randomly maximizing the number of high-scoring PGS alleles in a synthetic genome, as proposed by the article.