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    White Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropy

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    Author
    Ye, Zhenyao
    Mo, Chen
    Liu, Song
    Hatch, Kathryn S
    Gao, Si
    Ma, Yizhou
    Hong, L Elliot
    Thompson, Paul M
    Jahanshad, Neda
    Acheson, Ashley
    Garavan, Hugh
    Shen, Li
    Nichols, Thomas E
    Kochunov, Peter
    Chen, Shuo
    Ma, Tianzhou
    Show allShow less

    Date
    2021-10-14
    Journal
    Frontiers in Neuroscience
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3389/fnins.2021.738037
    Abstract
    Tobacco smoking is an addictive behavior that supports nicotine dependence and is an independent risk factor for cancer and other illnesses. Its neurogenetic mechanisms are not fully understood but may act through alterations in the cerebral white matter (WM). We hypothesized that the vertical pleiotropic pathways, where genetic variants influence a trait that in turn influences another trait, link genetic factors, integrity of cerebral WM, and nicotine addiction. We tested this hypothesis using individual genetic factors, WM integrity measured by fractional anisotropy (FA), and nicotine dependence-related smoking phenotypes, including smoking status (SS) and cigarettes per day (CPDs), in a large epidemiological sample collected by the UK Biobank. We performed a genome-wide association study (GWAS) to identify previously reported loci associated with smoking behavior. Smoking was found to be associated with reduced WM integrity in multiple brain regions. We then evaluated two competing vertical pathways: Genes → WM integrity → Smoking versus Genes → Smoking → WM integrity and a horizontal pleiotropy pathway where genetic factors independently affect both smoking and WM integrity. The causal pathway analysis identified 272 pleiotropic single-nucleotide polymorphisms (SNPs) whose effects on SS were mediated by FA, as well as 22 pleiotropic SNPs whose effects on FA were mediated by CPD. These SNPs were mainly located in important susceptibility genes for smoking-induced diseases NCAM1 and IREB2. Our findings revealed the role of cerebral WM in the maintenance of the complex addiction and provided potential genetic targets for future research in examining how changes in WM integrity contribute to the nicotine effects on the brain.
    Rights/Terms
    Copyright © 2021 Ye, Mo, Liu, Hatch, Gao, Ma, Hong, Thompson, Jahanshad, Acheson, Garavan, Shen, Nichols, Kochunov, Chen and Ma.
    Keyword
    causal inference
    mediation analysis
    nicotine
    pleiotropy
    white matter integrity
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17051
    ae974a485f413a2113503eed53cd6c53
    10.3389/fnins.2021.738037
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