Here, we attempted to expand on these previous discoveries by conducting the largest meta-analytic investigation of exonic rare variants to date. We conducted an exome-wide association meta-analysis of nicotine and alcohol use across 16 studies genotyped on the exome array, which genotypes low-frequency nonsynonymous and putative loss of function exonic variants. We combined these data with the UK Biobank, which includes approximately 400,000 individuals of European ancestry with genotype imputation to the Haplotype Reference Consortium(31) imputation reference panel and relevant smoking/drinking phenotypes. Sample sizes for well-imputed variants were thus enlarged and the availability of noncoding variants from UK Biobank enabled comprehensive analysis of genetic architecture(32) and fine mapping(33).
