With a maximum sample size ranging from 152,348 to 433,216, the present study is the largest study to date of low-frequency nonsynonymous and loss of function variants in smoking and alcohol use. Our meta-analytic study design combined studies genotyped on the exome array with imputed genotypes in the UK Biobank, allowed us to comprehensively evaluate the contribution of rare and low frequency variants to the etiology of tobacco and alcohol use. All told, we identified 171 genome-wide significant loci for the five phenotypes.
