Although the present study provided novel information regarding the phenotypic and molecular links of polysubstance dependence to suicidality, several limitations should be taken into account while evaluating the novelty of the results presented. Our phenotypic associations highlighted that polysubstance dependence and certain SDs are associated with specific suicidality patterns. Although we accounted for polysubstance comorbidity in our analysis, we did not include covariates related to other psychiatric traits associated with SDs and suicidality (i.e., MD and anxiety). Accordingly, future studies will be needed to understand the effect of psychiatric comorbidities on SD-suicidality associations. We combined genetic and phenotypic data from two large cohorts, but the sample size investigated is not large enough to investigate the polygenic architecture of complex traits like polysubstance dependence and suicidality. To date, there is limited availability of large cohorts informative to investigate SD genetics, especially when considering illegal drugs39,41. Although information from Yale-Penn and Army STARRS cohorts were previously combined to replicate genetic associations related to SD and suicidality8,11, the limited availability of information regarding polysubstance dependence in Army STARRS participants likely prevented us from
