Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals

Abstract

Cannabis is one of the most widely used drugs globally. Decriminalization of cannabis is further increasing cannabis consumption. We performed genome-wide association studies (GWASs) of lifetime (N=131,895) and frequency (N=73,374) of cannabis use. Lifetime cannabis use GWAS identified two loci, one near CADM2 (rs11922956, p=2.40E-11) and another near GRM3 (rs12673181, p=6.90E-09). Frequency of use GWAS identified one locus near CADM2 (rs4856591, p=8.10E-09; r² =0.76 with rs11922956). Both traits were heritable and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use associated cannabis use phenotypes in AllofUs participants. Phenome-wide association study of lifetime cannabis use PGS in a hospital cohort replicated associations with substance use and mood disorders, and uncovered associations with celiac and infectious diseases. This work demonstrates the value of GWASs of CUD transition risk factors.

Keywords: CADM2; GRM3; addiction; cannabis; genetic correlations; genome-wide association study; phenome-wide association study; polygenic score.

Figure 1.

Manhattan plots of A) lifetime cannabis use (N=131,895) and B) frequency of cannabis use (N=73,374). The horizontal line represents the significance threshold (p=5.00E-08). Nearest protein-coding genes (<1Mb) to significant loci (red dots) are labelled. For quantile-quantile plots and locus zoom plots, see Supplementary Fig. 2–4.

Figure 2.

SNP-based heritability and genetic correlation analysis comparisons across cannabis-related traits. A) Genetic correlations and h_2SNP across 23andMe lifetime cannabis use and frequency of cannabis use with ICC lifetime cannabis use and CUD from Levey et al. . h_2SNP±standard error shown in matrix diagonal (gray boxes), r_g±standard error in off-diagonal (white boxes). Correlation coefficients shown in heatmap color, with p value underneath in black. B) CUD requires progression through multiple pre-addiction stages, including experimental use, regular use, compulsive/harmful use, dependence, cessation attempts, and relapse. Aside from lifetime cannabis use as a proxy for experimental use and frequency of cannabis use as a proxy for regular use, which positively genetically correlate with CUD, most of these stages have not been genetically explored with GWAS.

Figure 3.

Comparison of genetic correlations across anthropometric (light gray), health (medium gray), and psychiatric (dark gray) traits between lifetime cannabis use (lanes 1 and 2) and frequency of cannabis use (lanes 3 and 4). Lanes 1 and 3 show r_g values calculated by LDSC, and lanes 2 and 4 show FDR-corrected p values. Only traits for which at least one cohort was FDR-significant are displayed. For a full list of correlations and trait names, see Supplementary Table 13. *reverse coded traits.

Figure 4.

Percent proportion of lifetime, daily, and problematic cannabis use variance attributable to lifetime cannabis use PGS, frequency of cannabis use PGS, or both (joint-PGS) in European and African AoU cohorts. Bonferroni-corrected significance of PGS contribution for single- and joint-PGS models (see Table 1, Supplementary Tables 15–16) shown above data label in its corresponding legend color (n.s. p>0.05, *p<0.05, **p<0.01, **p<0.001).

Figure 5.

Forest plot of FDR-significant phenome associations with lifetime cannabis use PGS unconditioned (UC), or with adjustment for cannabis use disorder (CUD), tobacco use disorder (TUD), or both (CUD-TUD). A) PheWAS results. B) LabWAS results. For full trait information, see Supplementary Tables 19–20.