AUTHOR=Zhang Xuefen , Lan Tongtong , Wang Tong , Xue Wei , Tong Xiaoran , Ma Tengfei , Liu Guifen , Lu Qing 

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

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00448

DOI=10.3389/fgene.2019.00448

ISSN=1664-8021

ABSTRACT=<p>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 <italic>CHRNA5</italic>. However, results from our analysis suggest heterogeneous effects of <italic>CHRNA6</italic> and <italic>CHRNB3</italic> on nicotine dependence in males and females. Following the gene-based analysis, we further conduct a joint association analysis of two gene clusters, <italic>CHRNA5</italic>-<italic>CHRNA3</italic>-<italic>CHRNB4</italic> and <italic>CHRNB3</italic>-<italic>CHRNA6</italic>. While both <italic>CHRNA5</italic>-<italic>CHRNA3</italic>-<italic>CHRNB4</italic> and <italic>CHRNB3</italic>-<italic>CHRNA6</italic> clusters are significantly associated with ND, there is a much stronger association of <italic>CHRNB3</italic>-<italic>CHRNA6</italic> with ND when considering heterogeneous effects in gender (<italic>p</italic>-value = 2.11E-07).</p>