This research has several limitations. First, although the polygenic scores explained more variance in these outcomes than previous iterations using smaller discovery GWAS, the variance explained by the largest meta-analysis of alcohol consumption to date, compiling data from ~1 million individuals, continued to be small (R2 ~ 0.015 in the current study, R2 ~ 0.025 in the original GWAS). Even larger discovery samples with better phenotyping will be necessary to create scores that explain the total SNP-based heritability. Secondly, although we found evidence of G × E, it does not rule out other confounding factors. Larger twin samples with genotypical data that allow for within-family designs will help to further account for possible environmental confounders shared across families (e.g. neighborhood factors, religiosity, socio-economic status; see Supporting information, Fig. S4 for sensitivity analyses). Longitudinal designs will allow us to understand more clearly the direction of effect and rule out explanations other than G × E. For example, those with high genetic propensity for alcohol misuse who experience low alcohol misuse may be more likely to enter a romantic relationship than those
