Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence.
Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence.
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DOI：
10.1007/s10519-016-9792-4
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发表时间：
2016-09
影响因子：
2.6
通讯作者：
Ehringer MA
中科院分区：
文献类型：
--
作者：
Kamens HM;Corley RP;Richmond PA;Darlington TM;Dowell R;Hopfer CJ;Stallings MC;Hewitt JK;Brown SA;Ehringer MA
烟碱乙酰胆碱受体基因（CHRN 基因）中常见的 SNP 与药物行为和人格特征相关，但罕见遗传变异的影响尚未得到很好的表征。该项目的目标是识别反社会药物依赖中心 (CADD) 和反社会药物依赖遗传学 (GADD) 样本中 CHRN 基因的新型罕见变异，并确定低频变异是否与反社会药物依赖相关。使用病例/对照设计选择了 114 人和 200 人的两个样本，包括反社会药物依赖表型分布的尾部。对每个样本中的每个受试者独立进行 16 个 CHRN 基因（CHRNA1-7、9、10、CHRNB1-4、CHRND、CHRNG、CHRNE）中所有变体的捕获、测序和分析。在使用基因组分析工具包 (GATK) 进行变异调用之前，使用 BWA 将测序读数与人类参考序列进行比对。使用 SKAT-O 和 C-alpha 分析低频变异（次要等位基因频率 < 0.05），以检查病例和对照中罕见变异的分布。在我们的较大样本中，使用 SKAT-O 和 C-alpha 发现，包含 CHRNA6/CHRNB3 基因簇的区域与疾病状态显着相关（未调整的 p 值 < 0.05）。与对照组相比，病例组中观察到更多的 CHRNA6/CHRNB3 基因区域低频变异。这些数据支持 CHRN 基因中的遗传变异和反社会药物行为的作用。
Common SNPs in nicotinic acetylcholine receptor genes (CHRN genes) have been associated with drug behaviors and personality traits, but the influence of rare genetic variants is not well characterized. The goal of this project was to identify novel rare variants in CHRN genes in the Center for Antisocial Drug Dependence (CADD) and Genetics of Antisocial Drug Dependence (GADD) samples and to determine if low frequency variants are associated with antisocial drug dependence. Two samples of 114 and 200 individuals were selected using a case/control design including the tails of the phenotypic distribution of antisocial drug dependence. The capture, sequencing, and analysis of all variants in 16 CHRN genes (CHRNA1-7, 9, 10, CHRNB1-4, CHRND, CHRNG, CHRNE) were performed independently for each subject in each sample. Sequencing reads were aligned to the human reference sequence using BWA prior to variant calling with the Genome Analysis ToolKit (GATK). Low frequency variants (minor allele frequency < 0.05) were analyzed using SKAT-O and C-alpha to examine the distribution of rare variants among cases and controls. In our larger sample, the region containing the CHRNA6/CHRNB3 gene cluster was significantly associated with disease status using both SKAT-O and C-alpha (unadjusted p values < 0.05). More low frequency variants in the CHRNA6/CHRNB3 gene region were observed in cases compared to controls. These data support a role for genetic variants in CHRN genes and antisocial drug behaviors.