Our findings demonstrate that TUD, as defined via EHR, was genetically correlated with traits derived from traditionally ascertained cohorts, including nicotine dependence via FTND and smoking cessation, providing clear evidence that the signal captured by TUD phecodes is valid. Of note, the genetic correlation between TUD and cigarettes smoked per day (CPD) was relatively modest (rg=0.44), suggesting that the genetic architectures of consumption and misuse are only partially overlapping, consistent with prior GWAS of alcohol and cannabis use and misuse (e.g.,23,26,48). This contrasts with earlier observations for FTND and CPD, for which the genetic correlation was almost at unity (rg=0.95).27 This shows that TUD captures features beyond the frequency of smoking or severity of nicotine dependence. Although FTND and TUD were more strongly genetically correlated (rg=0.63), in general, we observed that TUD PGS was more predictive of DSM-defined tobacco dependence and a plethora of comorbid traits in the Yale-Penn sample, than FTND PGS. The only exception was for smoke after waking, which was more strongly associated with FTND PGS, likely because time-to-first cigarette is one of the FTND items. TUD
