CHRNA2 is related to other nicotine receptor genes that have been identified as risk loci for nicotine dependence and smoking behavior27. It is therefore relevant to question if our finding is confounded by smoking. In the iPSYCH cohort there is no avaible information about smoking behavior. As much as 70-90% of cannabis users are reported also to smoke cigarettes28, which impose the risk of confounding. However, smoking is also highly comorbid with psychiatric disorders29, which is prevalent among the control group (66,79% were diagnosed with at least one of the major psychiatric disorders studied in iPSYCH; Supplementary Table 1). Since we expect smoking to be prevalent both among cases and the control group, it is unlikely that smoking alone would generate the high effect size we observe for the risk locus on chromosome 8. However, in the recent GWAS meta-analysis of smoking30 including more than 1.2 mill people the CUD risk locus is genome-wide significantly associated with smoking, with the CUD risk allele increasing risk for smoking initiation, younger age at smoking initiation and continuation of smoking, but it is
