Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence.
Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence.
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作者：
Zuo L;Garcia-Milian R;Guo X;Zhong C;Tan Y;Wang Z;Wang J;Wang X;Kang L;Lu L;Chen X;Li CR;Luo X
尼古丁乙酰胆碱受体（nAChRs）在尼古丁依赖（ND）中起重要作用，并影响吸烟者的日吸烟量（CPD）。我们汇编了在不同研究中重复的烟碱胆碱能受体基因（CHRN）和ND/CPD之间的关联，回顾了这些风险基因在人类/小鼠大脑中的表达，并使用人类和小鼠大脑的独立样本验证了它们的表达。使用顺式eQTL分析检查或使用一系列生物信息学分析预测复制的风险变体的潜在功能。我们在三个基因组区域（CHRNB 3-A6，CHRNA 5-A3-B4和CHRNA 4）的六个基因的19个SNP上发现了ND/CPD的重复和显著关联。这六个风险基因在人类/小鼠大脑的至少18个不同区域中表达，并在我们独立的人类和小鼠大脑样本中得到验证。风险变异可能影响风险基因的转录、表达和剪接，改变RNA二级结构或蛋白质结构。我们的结论是，CHRNB 3-A6，CHRNA 5-A3-B4，CHRNA 4和ND/CPD之间的重复关联是非常强大的。需要更多的研究来研究这些遗传变异如何导致ND/CPD的风险。
It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4, CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD.
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