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

doi:10.3389/fgene.2019.00448

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

Biostatistics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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).

Original language	English
Article number	448
Journal	Frontiers in Genetics
Volume	10
Issue number	MAY
DOIs	https://doi.org/10.3389/fgene.2019.00448
State	Published - 2019

Bibliographical note

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.

Funding

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).

Funders	Funder number
Environment and Health Initiative
GEI Consultants Inc	U01 HG004422
Genetics and Environment
National Institutes of Health (NIH)
National Institute on Drug Abuse	R01DA043501
U.S. National Library of Medicine	R01LM012848
Environment and Health Fund
Faculty of Science, Agriculture and Engineering, Newcastle University

Keywords

Genetic heterogeneity
NAChRs genes
Nicotine dependence
SAGE
Weighted U

ASJC Scopus subject areas

Molecular Medicine
Genetics
Genetics(clinical)

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10.3389/fgene.2019.00448

Cite this

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title = "Considering genetic heterogeneity in the association analysis finds genes associated with nicotine dependence",

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).",

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AU - Liu, Guifen

AU - Lu, Qing

N1 - 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.

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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