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Background  The  CHRNA5/A3/B4  gene locus is associated with nicotine dependence and other smoking related disorders. While the non-synonymous  CHRNA5  variant rs16969968 appears to be the main risk factor, linkage disequilibrium (LD) bins in the gene cluster carry frequent variants that regulate expression. Pairwise LD and haplotype analyses had identified at least three haplotype tagging SNPs including rs16969968 as main genetic risk factors. Searching for variants with evidence of regulatory functions, we have reported interactions between  CHRNA5  and  CHRNA3  enhancer variants (tagged by rs880395 and rs1948, respectively) and rs16969968, forming 3-SNP haplotypes and diplotypes that may more accurately reflect the cluster’s combined effects on nicotine dependence (Barrie et al., Hum Mutat 38:112–9, 2017). Here we address further contributions by variants affecting  CHRNB4 , a possibly limiting component of nicotinic receptors.    Results  We identify an LD bin (tagged by rs4887074) associated with expression of  CHRNB4 . Additive logistic regression models indicate that rs4887074 is associated with nicotine dependence and modulates the effect of rs16969968 in GWAS datasets (COGEND, UW-TTURC, SAGE). 4-SNP haplotype and diplotype analyses (rs880395-rs16969968-rs1948 -rs4887074) yield nicotine dependence risk values that further differentiate those obtained with the 3-SNP model. Moreover, both the main  G  allele of rs16969968 and the minor  G  allele of rs4887074 (associated with reduced expression of  CHRNB4 ), residing predominantly on common haplotypes that are protective, represent significant allele-specific variance QTLs, indicating that they interact with each other.    Conclusions  These results indicate rs4887074 is associated with  CHRNB4  expression, and along with two regulatory variants of  CHRNA3  and  CHRNA5 , modulates the effect of rs16969968 on nicotine dependence risk. Assignable to individuals because of strong LD structures, 4-SNP haplotypes and diplotypes serve to assess the combined genetic influence of this multi-gene cluster on complex traits, accounting for complex LD relationships and tissue-specific genetic effects ( CHRNA5/3 ) relevant to the traits analyzed. The 4-SNP haplotypes account at least in part for previous tagging SNPs, including the highly GWAS-significant rs6495308, located in a distinct pair-wise LD bin but included in protective 4-SNP haplotypes. Our approach refines and integrates the cluster’s overall genetic influence, an important variable when integrating the genetics of multiple genomic loci.    Electronic supplementary material  The online version of this article (10.1186/s12864-018-5219-3) contains supplementary material, which is available to authorized users.

Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence