effects of missense rare variants at conserved residues in CHRNB4. They examined in vitro the functional effects of the three major association signal contributors (i.e., T375I and T91I in CHRNB4 and R37H in CHRNA3), finding that the minor alleles of the studied SNPs increased the cellular response to nicotine. The two rare variants in CHRNB4 were confirmed to augment nicotine-mediated α3β4 nAChR currents in hippocampal neurons, as did a third variant, D447X, in the report of Slimak et al.136 The fourth SNP they analyzed, R348C, reduced nicotine currents. They also observed that habenular expression of the β4 gain-of-function allele T374I resulted in strong aversion to nicotine in mice, whereas transduction of the β4 loss-of-function allele R348C failed to induce nicotine aversion. Later, Doyle et al.137 reported an interesting rare variant in CHRNA5 that could result in nonsense-mediated decay of aberrant transcripts in 250 AA heavy smokers. And recently, Yang et al.138 performed a targeted sequencing study with the goal of determining both the individual and the cumulative effects of rare and common variants in 30 candidate genes implicated in ND. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3, and ARRB2 were found to be significantly associated
