Abstract
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).
Highlights
Cigarette smoking is a leading cause of preventable disease, contributing to 5 million premature deaths worldwide each year
Considering that the genetic etiology of nicotine dependence (ND) could be heterogeneous in gender (Li et al, 2003), we applied the heterogeneity weighted U (HWU) method to 26 genes previously reported to be associated with ND, investigating potential genetic heterogeneity of these genes in males and females
By considering genetic heterogeneity in gender, the analysis identified 24 genes significantly associated with cigarettes smoked per day (CPD) (Table 3)
Summary
Cigarette smoking is a leading cause of preventable disease, contributing to 5 million premature deaths worldwide each year. Genetic Heterogeneity in Nicotine Dependence studies (GWAS) in identifying ND-associated genetic variants (Furberg et al, 2010; Sullivan et al, 2010; Wei et al, 2012). Studies have found the potential role of CYP2A6 variants (e.g., rs4105144) in nicotine metabolism (Thorgeirsson et al, 2010) Despite these achievements, the currently confirmed genetic variants only account for a small proportion of ND variation and a large proportion of ND loci remain undetected. Despite the strong evidence of heterogeneity in ND, investigating genetic variants with heterogeneous effects in ND remains a great challenge, due to issues such as multiple testing and reduced sample size in each subgroup. To study the genetic heterogeneity of ND, we started with a gene-based association analysis of 26 ND-related genes, considering their heterogeneous effects in males and females.
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