We report the results from a genetic association test between nearly 100,000 rare nonsynonymous exonic SNPs with 5 measures of behavioral disinhibition, as well as three measures of substance use in individuals exposed to the relevant substance. Tests of genetic association, whether single variant tests or gene-based burden tests, revealed no significant associations. Additional inspection of 172 candidate genes, of which 151 contained polymorphic variation in this sample, also revealed no significant association. One SNP was statistically significant only after restricting tests to nonsynonymous variants within genes previously implicated in drinking and smoking by GWAS meta-analysis. This variant was associated with nicotine dependence among individuals exposed to nicotine. The variant is located in the dopamine beta-hydroxylase gene (DBH), a long-standing candidate gene for addiction due to dopamine’s clear involvement in the rewarding effects of drugs of abuse(44). A variant within this gene was previously found to be associated with smoking cessation by the TAG consortium(22). Our nicotine phenotype is not cessation per se and that, along with the nominally-associated p-value, suggests that this is a spurious finding. This variant will require substantial verification in larger samples.
