There are three key implications from our study. First, we found a statistically significant association between cannabis PRS and trajectory membership, and the effect size (Δ conditional R2 up to 3.6%) was consistent with other PRS analyses21. Thus, genetic propensity to cannabis initiation derived from a large, heterogeneous discovery sample appears to differentiate between classes derived from frequency of cannabis use in an ascertained, longitudinal cohort. Interestingly, lifetime cannabis use was not significantly related to PRS. However, maximum frequency of use and DSM5 CUD were associated with PRS in the larger sample of 1,840. It is possible that even though the discovery GWAS was aimed at assessing genetic propensity to lifetime use, that polygenic liability is better captured along a developmental spectrum in these data. While, to some extent, the classes differed in severity of use (e.g., CUD), associations with class membership (e.g., high vs. no-low) far exceeded cross-sectional associations with CUD, suggesting that class membership in this young and ascertained sample may be a superior index of genetic propensity than cross-sectional indices alone.
