we hypothesized that functional annotation information like DHS location could be used to improve the predictive ability of polygenic scores. Using alcohol problems as our primary outcome, we expected that polygenic scores based on SNPs in regulatory regions (DHSs) would provide stronger predictive power (i.e., account for more variance) compared to conventional, unselected, genome-wide polygenic scores that included a mixture of DHS SNPs and non-DHS SNPs. We focus specifically on localization in DHSs in view of recent evidence that SNPs with lower p values in our discovery sample GWAS were more likely to be in DHS regions (versus non-DHS regions) (Edwards et al., 2015), as well as broader evidence from genomic partitioning analyses that DHS SNPs accounted for the majority (79%) of the heritability across 11 common diseases (Gusev et al., 2014). Additionally, in the absence of existing knowledge about what specific functional annotations would be most advantageous to inform polygenic scores, DHS status provides a non-specific tool for a first look into whether this approach holds promise.
