In the survival analysis, ten SNPs on CHRNA5/B4/A3 were used to predict the risk to engage in using tobacco, alcohol, cannabis, inhalants, and/or other substance between ages 5 and 19. Several SNPs were significant or marginally significant predicting onset of alcohol, cannabis, inhalants, and “other substances” after correcting for multiple testing. This result indicates a general role of the CHRNA5/B4/A3 gene cluster that is not limited to nicotine dependence (ND) and ND related phenotypes. The latent class analysis, which modeled first use of the different substances jointly, showed a clear effect of rs11637630 and rs8040868 discriminating between early and later onset of first use. The effect of rs8040868 corroborates previous findings.