This is the first study to report a genome-wide significant risk locus, for diagnosed CUD replicated in an independent cohort. The locus is located intergenic on chromosome 8 (index variant rs56372821) and has an odds ratio of 0.73, an effect size in line with findings for other complex disorders19,33. PRS supported a high consistency of the CUD phenotypes analysed in the discovery and replication cohorts from iPSYCH and deCODE, respectively, and supported that the GWAS results reflect association with CUD and not comorbid psychiatric disorders in the iPSYCH cohort. This also holds for the risk locus, where carefull dissection with respect to the distribution of effect sizes for the index variant (rs56372821) over co-morbid subgroups revealed no confounding from psychiatric disorders. This included exclusion of individuals with schizophrenia, which still revelaed genome-wide significant association of rs56372821 with CUD. This supports the proposed hypothesis that the genome-wide significant signal observed for the CUD risk locus in schizophrenia19 could be driven by a sub-group of schizophrenia cases having CUD.
