We note several limitations of cross-trait LD Score regression as an estimator of genetic correlation. First, cross-trait LD Score regression requires larger sample sizes than methods that use individual genotypes in order to achieve equivalent standard error. Second, cross-trait LD Score regression is not currently applicable to samples from recently-admixed populations. Third, we have not investigated the potential impact of assortative mating on estimates of genetic correlation, which remains as a future direction. Fourth, methods built from polygenic models, such as cross-trait LD Score regression and REML, are most effective when applied to traits with polygenic genetic architectures. For traits where significant SNPs account for a sizable proportion of heritability, analyzing only these SNPs can be more powerful. Developing methods that make optimal use of both large-effect SNPs and diffuse polygenic signal is a direction for future research.
