Genes and Disease Program, Centre for Genomic Regulation and UPF and Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública, Catalonia, Spain.
Genes Brain Behav. 2012 Aug;11(6):704-11. doi: 10.1111/j.1601-183X.2012.00815.x. Epub 2012 Jul 17.
The Neurexin 3 gene (NRXN3) has been associated with dependence on various addictive substances, as well as with the degree of smoking in schizophrenic patients and impulsivity among tobacco abusers. To further evaluate the role of NRXN3 in nicotine addiction, we analyzed single nucleotide polymorphisms (SNPs) and a copy number variant (CNV) within the NRXN3 genomic region. An initial study was carried out on 157 smokers and 595 controls, all of Spanish Caucasian origin. Nicotine dependence was assessed using the Fagerström index and the number of cigarettes smoked per day. The 45 NRXN3 SNPs genotyped included all the SNPs previously associated with disease, and a previously described deletion within NRXN3. This analysis was replicated in 276 additional independent smokers and 568 controls. Case-control association analyses were performed at the allele, genotype and haplotype levels. Allelic and genotypic association tests showed that three NRXN3 SNPs were associated with a lower risk of being a smoker. The haplotype analysis showed that one block of 16 Kb, consisting of two of the significant SNPs (rs221473 and rs221497), was also associated with lower risk of being a smoker in both the discovery and the replication cohorts, reaching a higher level of significance when the whole sample was considered [odds ratio = 0.57 (0.42-0.77), permuted P = 0.0075]. By contrast, the NRXN3 CNV was not associated with smoking behavior. Taken together, our results confirm a role for NRXN3 in susceptibility to smoking behavior, and strongly implicate this gene in genetic vulnerability to addictive behaviors.
神经连接素 3 基因（NRXN3）与对各种成瘾物质的依赖有关，也与精神分裂症患者的吸烟程度和烟草滥用者的冲动有关。为了进一步评估 NRXN3 在尼古丁成瘾中的作用，我们分析了 NRXN3 基因组区域内的单核苷酸多态性（SNP）和拷贝数变异（CNV）。最初的研究在 157 名吸烟者和 595 名对照者中进行，所有对照者均为西班牙白种人。使用 Fagerström 指数和每天吸烟的支数评估尼古丁依赖。所测定的 45 个 NRXN3 SNP 包括以前与疾病相关的所有 SNP，以及 NRXN3 内的一个以前描述的缺失。这项分析在 276 名额外的独立吸烟者和 568 名对照者中进行了复制。在等位基因、基因型和单倍型水平上进行病例对照关联分析。等位基因和基因型关联测试表明，NRXN3 的三个 SNP 与较低的吸烟风险相关。单倍型分析表明，由两个有意义的 SNP（rs221473 和 rs221497）组成的 16 Kb 块也与发现和复制队列中较低的吸烟风险相关，当考虑整个样本时，其达到更高的显著水平[比值比=0.57（0.42-0.77），置换 P=0.0075]。相比之下，NRXN3 CNV 与吸烟行为无关。总之，我们的结果证实了 NRXN3 在易感性吸烟行为中的作用，并强烈暗示该基因在成瘾行为的遗传易感性中起作用。
