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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). [ABSTRACT FROM AUTHOR]