Another explanation for the negative genetic association is that it is due to a third, underlying variable influencing both AN without binge-eating and smoking. In the largest GWAS of smoking phenotypes, positive genetic correlations were observed between smoking initiation and cigarettes per day with multiple cardiometabolic traits, including type 2 diabetes and fasting glucose (Liu et al., 2019). These same metabolic traits were negatively genetically correlated with AN (Duncan et al., 2017, Watson et al., in press). Thus, the patterns of rgs point to metabolic, rather than psychiatric, factors in influencing the apparent genetic association between smoking phenotypes and AN. However, the associations could also reflect adoption of unhealthy lifestyles that promote obesity and are correlated with smoking. In addition, the rgs between smoking and BMI, as well as AN and BMI, could reflect underlying disinhibitory pathways, as variants associated with BMI show enrichment in the central nervous system (Goodarzi, 2018). The current approach is not designed to disentangle these putative etiological mechanisms, but our findings do encourage careful study of the specific relationships between eating and substance use disorders.
