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
Maryland Psychiatric Research Center, Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.
Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.
Front Neurosci. 2021 Oct 14;15:738037. doi: 10.3389/fnins.2021.738037. eCollection 2021.
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 and . 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.
吸烟是一种成瘾行为，会导致尼古丁依赖，并且是癌症和其他疾病的独立危险因素。其神经遗传学机制尚未完全明确，但可能通过大脑白质（WM）的改变起作用。我们推测，垂直多效性途径（即基因变异影响一个性状，该性状又影响另一个性状）将遗传因素、大脑WM完整性和尼古丁成瘾联系起来。我们在英国生物银行收集的一个大型流行病学样本中，使用个体遗传因素、通过分数各向异性（FA）测量的WM完整性以及与尼古丁依赖相关的吸烟表型（包括吸烟状态（SS）和每日吸烟量（CPD））来验证这一假设。我们进行了全基因组关联研究（GWAS），以确定先前报道的与吸烟行为相关的基因座。研究发现，吸烟与多个脑区的WM完整性降低有关。然后，我们评估了两条相互竞争的垂直途径：基因→WM完整性→吸烟与基因→吸烟→WM完整性，以及一条水平多效性途径，即遗传因素独立影响吸烟和WM完整性。因果途径分析确定了272个多效性单核苷酸多态性（SNP），其对SS的影响由FA介导，还有22个多效性SNP，其对FA的影响由CPD介导。这些SNP主要位于吸烟诱导疾病的重要易感基因中。我们的研究结果揭示了大脑WM在维持复杂成瘾中的作用，并为未来研究WM完整性变化如何导致尼古丁对大脑的影响提供了潜在的遗传靶点。
