Advances in sequencing, genotyping, and genotype imputation now allow cost effective investigation of rare and low frequency variants. Compared to common variants (minor allele frequency [MAF] > 1%) most commonly used in genome-wide association studies (GWAS), rare variants have greater potential to elucidate biological mechanisms of complex traits, including substance use and addiction(8, 9). In particular, nonsynonymous and loss of function (LoF) coding variants, which result in the loss of normal function of a protein, may have greater phenotypic impact and more direct mechanistic interpretation than other variants that do not have obvious biological consequences(10, 11).
