In further exploratory analysis, we evaluated nonsynonymous variants with minor allele count (MAC)≥4 and MAF≤.05. We did this because common variants (MAF>.05) have been tested elsewhere and there is very limited power to detect effects for variants with MAC<4, which is why burden tests are used(35). Evaluating this restricted SNP set lowers the Bonferroni threshold to 8.06×10−7, and resulted in one SNP at 5:73207116 in the GRNEF gene associated with nicotine dependence (reference allele=G; alternate=A; MAC=12, effect=1.49; p=6.9×10−7). The QQ plot is in Figure S14 (see Supplement 1). We report this SNP only a suggestive finding. Using Snipper(43), we found no evidence in the literature that this region has previously been linked to relevant phenotypes.
