As an alternative to the candidate-gene approach, the genome-wide association study (GWAS) is a hypothesis-free method that aims to detect novel genetic variants involved in complex traits. To date, three GWASs of cannabis use phenotypes have been published: one GWAS of cannabis dependence in 708 cannabis-dependent individuals and 2346 controls;25 a GWAS meta-analysis of lifetime cannabis use based on two studies with a combined sample size of 10 091 individuals (40.7% users);26 and a recent GWAS of lifetime cannabis use and age of cannabis use onset based on a sample of 6744 individuals (of whom 20% were users).27 None of the studies identified any genome-wide significant associations. This was likely due to the small effect sizes typical of common variants underpinning highly polygenic traits,28 thereby indicating a need for larger sample sizes. In this context, the success of larger GWASs and international consortia examining a variety of complex traits is encouraging.29 For example, multiple large meta-analyses of GWA results for number of cigarettes smoked per day have independently identified associations on chromosome 15q25 spanning the α5, α3 and β4 nicotinic receptor subunit gene clusters (CHRNA5, CHRNA3, CHRNB4).30, 31, 32
