We showed that the rare variants (MAF≤1%) together explain 1.0% - 2.2% of the phenotypic variance for the five traits, amounting to 11–18% of the total SNP heritability. A number of putatively causal low frequency nonsynonymous variants in novel genes were identified through two complementary fine mapping techniques. These include a variant known to affect alpha-1 antitrypsin deficiency in SERPINA1. The effect of the risk allele resulted in a decrease in drinks per week. One interpretation is that this variant leads to impaired liver function through alpha-1 antitrypsin deficiency which, in turn, reduces alcohol consumption. Interestingly, neither this particular variant or the locus surrounding it was associated with smoking phenotypes, even though alpha-1 antitrypsin deficiency also affects lung function over time. Other mechanisms by which SERPINA1 exerts its effect on alcohol consumption are certainly possible. Another novel nonsynonymous variant was in neuron navigator 2 (NAV2), associated with smoking initiation. NAV2 has not previously been associated with substance use or addiction. Given its suspected involvement in neuronal growth and migration, a putatively causal nonsynonymous variant is a strong candidate for functional
