Results of gene-based tests are provided in Table 2. A novel gene, rho guanine nucleotide exchange factor 37 (ARHGEF37), was associated with Age of Initiation of Smoking (p=1.9×10−6). ARHGEF37 has not been widely studied and its function in not well known. Another novel gene without an immediate biological interpretation, was HEAT Repeat Containing 5A (HEATR5A), associated with Smoking Initiation (p=1.4×10 −8). We also discovered a significant gene-based association between known alcohol metabolism gene ADH1C and Drinks per Week (p=1.4×10−27 and p=1.9×10−40 from the burden and SKAT tests, respectively). Finally, even with relaxed p-value thresholds, we failed to replicate genes identified in previous rare variant association studies referenced in the introduction (Table S4), with the exception of ADH1C and CHRNA5, two loci long known to be associated with alcohol use and smoking, respectively.
