Fourth, we found that Consumption PRS was strongly associated with AUD even in higher-risk cohorts like COGA. This demonstrates the important downstream effects of allowing items to have different weights in phenotype construction. Whereas our current and previous PRS for AUDIT-C have been disproportionately influenced by a single item (frequency of consumption)(42), our Consumption PRS was composed of the genetic effects shared among all consumption-focused items. The Consumption and Problems PRSs were both strongly associated with AUD in UK Biobank – even when both scores were entered in the same model. In COGA, both Consumption and Problems PRSs were associated with AUD, but Consumption PRS was more strongly associated than Problems PRS. The increased influence of binge drinking (item 3), which had a large factor loading on Consumption, may be partially responsible for these stronger associations in a high-risk sample. However, it is perhaps more likely that these differences might be simply explained by differences in item endorsement and thus predictive power of the discovery GWASs (e.g., Consumption had a greater mean χ2 than Problems).
