Considering genetic heterogeneity in the association analysis finds genes associated with nicotine dependence

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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).

Original languageEnglish
Article number448
JournalFrontiers in Genetics
Issue numberMAY
StatePublished - 2019

Bibliographical note

Funding Information:
This research was supported, in part, by the National Institute on Drug Abuse under Award Number R01DA043501 and the National Library of Medicine under Award Number R01LM012848, and also support for the study of addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422).

Publisher Copyright:
Copyright © 2019 Zhang, Lan, Wang, Xue, Tong, Ma, Liu and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


  • Genetic heterogeneity
  • NAChRs genes
  • Nicotine dependence
  • SAGE
  • Weighted U

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)


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