PRS are increasingly being employed to assess genetic relationships among phenotypes, especially those not measured at GWAS scale. PRS can hypothetically be used to examine cross-trait correlation and dissect biological pathways for phenotypes that have been measured at sufficient scale to generate well-powered GWAS summary statistics, but more appropriate methods have been specifically designed for these purposes. For example, heritability can be partitioned into functional elements with any biological annotation using LD score regression (33). For all analyses, it is important to consider sample ascertainment, and potential biases relevant to inferring the relationships between phenotypes. A summary of the methodological approaches used by various software packages to predict genetic risk, assess heritability, and compute genetic correlation among traits is described in Table 1.
