We found the nicotinic gene cluster CHRNA5–A3–B4 to be significantly associated with SmkInit12 with a fine-mapped 90% credible interval that shrank from 53 variants in EUR-stratified results to just two variants in multi-ancestry results (rs2869055 and rs28438420; Supplementary Table 4). These variants are not in high LD (r2 = 0.31 for both variants) with the well-known variant rs16969968 in this gene cluster. By contrast, this locus was fine-mapped to two variants in high LD with rs16969968 for CigDay (r2 = 0.84 and 0.86), suggesting that the variants underlying this signal for smoking initiation may be distinct from those for cigarettes per day. We also found a novel association between SmkInit and CACNA1B, which encodes a voltage-gated calcium channel (Cav2.2) that controls neuronal neurotransmitter release and has been associated with cocaine reinstatement13, increased aggression and vigilance, and reduced startle and exploration14. CACNA1B is linked to multiple psychiatric disorders, including schizophrenia, bipolar disorder and autism spectrum disorders15–17.
