The proportion of variance in liability to cannabis use that could be explained by the aggregated effect of the SNPs (h2SNPs) was estimated using LD-Score regression analysis60. The method is based on the premise that an estimated SNP effect-size includes effects of all SNPs in linkage disequilibrium (LD) with that SNP. A SNP that tags many other SNPs will have a higher probability of tagging a causal genetic variant compared to a SNP that tags few other SNPs. The LD score estimates the amount of genetic variation tagged by a SNP within a specific population. Accordingly, assuming a trait with a polygenic architecture, SNPs with a higher LD-score have on average stronger effect sizes than SNPs with lower LD-scores. When regressing the effect size from the association analysis against the LD score for each SNP, the slope of the regression line provides an estimate of the proportion of variance accounted for by all analysed SNPs60. For this analysis, we included 1,179,898 SNPs that were present in all cohorts and the HapMap 3 reference panel. Standard LD scores were used as provided by Bulik-Sullivan et al.60 based on the Hapmap 3 reference panel, restricted to European populations61.
