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While substantial progress has been made in finding genetic variants associated with nicotine dependence (ND), a large proportion of the genetic variants remain undiscovered. The current research focuses have shifted toward uncovering rare variants, gene-gene/gene-environment interactions, and structural variations predisposing to ND, the impact of genetic heterogeneity in ND has been nevertheless paid less attention. The study of genetic heterogeneity in ND not only could enhance the power of detecting genetic variants with heterogeneous effects in the population but also improve our understanding of genetic etiology of ND. As an initial step to understand genetic heterogeneity in ND, we applied a newly developed heterogeneity weighted U (HWU) method to 26 ND-related genes, investigating heterogeneous effects of these 26 genes in ND. We found no strong evidence of genetic heterogeneity in genes such as  CHRNA5 . However, results from our analysis suggest heterogeneous effects of  CHRNA6  and  CHRNB3  on nicotine dependence in males and females. Following the gene-based analysis, we further conduct a joint association analysis of two gene clusters,  CHRNA5 - CHRNA3 - CHRNB4  and  CHRNB3 - CHRNA6 . While both  CHRNA5 - CHRNA3 - CHRNB4  and  CHRNB3 - CHRNA6  clusters are significantly associated with ND, there is a much stronger association of  CHRNB3 - CHRNA6  with ND when considering heterogeneous effects in gender ( p -value = 2.11E-07).

Considering Genetic Heterogeneity in the Association Analysis Finds Genes Associated With Nicotine Dependence