These findings should be interpreted in light of a few limitations. First and foremost, our analyses include only data from participants of European ancestry, thereby limiting the generalizability of our results. This was a practical choice as we relied on previously published GWAS and sufficiently powered GWAS of non-European ancestry samples are not yet available for these outcomes. Second, although our sensitivity analyses indicated that this phenotype did not exert undue influence on the composition of externalizing, we note that sources of individual differences in age at first sex might differ across populations45,46. Third, results for individual residual analyses are dependent on both the power of the original GWAS indicator and the loadings of that indicator on its factor, which determines how much variance is leftover to analyze. Finally, although SUDs manifest the strongest relationships with other externalizing phenotypes, they also have a complex interface with many other forms of psychopathology, including internalizing47,48, which are not modeled in the current study.
