Gene-based tests improve power by aggregating effects of rare variants. While no genes reached our Bonferroni-adjusted P-value threshold, we identified three candidate genes with multiple rare variant associations for future replication: calcitonin gene-related peptide-receptor component (CRCP) with CPD and CHRNA2 and MMP17 with pack-years (Supp. Table 6; also see ‘Genes of Interest’ section in Supp. Material). CRCP’s protein product is expressed in brain tissues amongst others and functions as part of a receptor complex for a neuropeptide that increases intracellular cyclic adenosine monophosphate levels [56]. MMP17 encodes a matrix metalloproteinase that is also expressed in the brain and is a member of the peptidase M10 family, and proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes [57]. Given, we were not able conclusively to identify rare variant associations, even larger studies, are required to identify rare variants associated with smoking behaviours. In addition, phenotypes such as cotinine levels [58] and nicotine metabolism speed [59] could be interrogated using methods such as MTAG [60] to improve power.
