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dc.contributor.authorYe, Zhenyao
dc.contributor.authorMo, Chen
dc.contributor.authorLiu, Song
dc.contributor.authorHatch, Kathryn S
dc.contributor.authorGao, Si
dc.contributor.authorMa, Yizhou
dc.contributor.authorHong, L Elliot
dc.contributor.authorThompson, Paul M
dc.contributor.authorJahanshad, Neda
dc.contributor.authorAcheson, Ashley
dc.contributor.authorGaravan, Hugh
dc.contributor.authorShen, Li
dc.contributor.authorNichols, Thomas E
dc.contributor.authorKochunov, Peter
dc.contributor.authorChen, Shuo
dc.contributor.authorMa, Tianzhou
dc.date.accessioned2021-11-03T18:30:54Z
dc.date.available2021-11-03T18:30:54Z
dc.date.issued2021-10-14
dc.identifier.urihttp://hdl.handle.net/10713/17051
dc.description.abstractTobacco 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.en_US
dc.description.urihttps://doi.org/10.3389/fnins.2021.738037en_US
dc.language.isoenen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.ispartofFrontiers in Neuroscienceen_US
dc.rightsCopyright © 2021 Ye, Mo, Liu, Hatch, Gao, Ma, Hong, Thompson, Jahanshad, Acheson, Garavan, Shen, Nichols, Kochunov, Chen and Ma.en_US
dc.subjectcausal inferenceen_US
dc.subjectmediation analysisen_US
dc.subjectnicotineen_US
dc.subjectpleiotropyen_US
dc.subjectwhite matter integrityen_US
dc.titleWhite Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropyen_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fnins.2021.738037
dc.identifier.pmid34720862
dc.source.volume15
dc.source.beginpage738037
dc.source.endpage
dc.source.countrySwitzerland


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