Genomewide association study identifies a novel locus for cannabis dependence

Despite moderate heritability, only one study has identified genomewide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genomewide association study (GWAS) data on 2,080 DSM-IV cannabis dependent cases and 6,435 cannabis exposed controls of European descent. A cluster of correlated single nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genomewide significant (lowest p = 1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African-American (896 cases and 1591 controls; p=0.03) but not European-American (781 cases and 1905 controls) participants. The combined meta-analysis (3,757 cases and 9,931 controls) indicated trend-level significance for rs1409568 (p=2.85E-7). No genomewide significant loci emerged for cannabis dependence criterion count (n=8,050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 European-American college students (fwe-p=.007). The identification and characterization of genomewide significant loci for cannabis dependence is amongst the first steps towards understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.