Common Genetic Variants in ARNTL and NPAS2 and at Chromosome 12p13 are Associated with Objectively Measured Sleep Traits in the Elderly
Common Genetic Variants in ARNTL and NPAS2 and at Chromosome 12p13 are Associated with Objectively Measured Sleep Traits in the Elderly
复制标题
DOI：
10.5665/sleep.2466
复制
发表时间：
2013-03-01
期刊：
影响因子：
5.6
通讯作者：
Tranah, Gregory J.
中科院分区：
文献类型：
--
作者：
Evans, Daniel S.;Parimi, Neeta;Tranah, Gregory J.
研究目的：确定生物钟基因通路中常见的遗传变异与客观测量的活动记录睡眠和活动节律特征之间的关联。设计：两个基于人群的老年参与者队列的遗传关联研究：骨质疏松性骨折研究（SOF）和男性骨质疏松性骨折研究（MrOS）。设置：基于人群。参与者：SOF参与者（n = 1，407，100%女性，平均年龄84岁）和MrOS受试者（n = 2，527，100%男性，平均年龄77岁）与体动记录仪和基因型数据。干预：N/A。测量和结果：使用529个单核苷酸多态性（SNP）捕获30个候选基因中的常见遗传变异。睡眠和活动节律的特点，客观地测量手腕活动记录仪。在含有候选基因GNB 3的染色体12 p13上的高度连锁不平衡区域中，rs 1047776 A等位基因和rs 2238114 C等位基因与睡眠发作后较高的觉醒显著相关（荟萃分析：rs 1047776 P-ADD = 2 x 10（-5），rs 2238114 P-ADD = 5 x 10（-5））和较低的LRRC 23基因表达（rs 1047776：. =-0.22，P = 0.02; rs2238114：. =-0.50，P = 5 × 10（-8））。在MrOS参与者中，ARNTL和NPAS 2（编码结合伴侣的基因）中的SNP与较晚的睡眠和觉醒时间相关（睡眠开始时间：ARNTL rs3816358 P-2DF = 1 x 10（-4），NPAS 2 rs3768984 P-2DF = 5 x 10（-5）;觉醒时间：rs3816358 P-2DF = 3 × 10（-3），rs3768984 P-2DF = 2 × 10（-4）），SNP相互作用显著（睡眠起始时间P-INT = 0.003，觉醒起始时间P-INT = 0.001）。在MrOS队列中复制了CLOCK基因中的SNP关联，并且在先前报道的研究中rs3768984与睡眠时间相关。聚类分析确定了四个集群的遗传associations.Conclusions：这些研究结果支持的作用，共同的遗传变异的时钟基因在调节相互相关的睡眠性状在老年人。
Study Objectives: To determine the association between common genetic variation in the clock gene pathway and objectively measured actigraphic sleep and activity rhythm traits.Design: Genetic association study in two population-based cohorts of elderly participants: the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men (MrOS) study.Setting: Population-based.Participants: SOF participants (n = 1,407, 100% female, mean age 84 years) and MrOS participants (n = 2,527, 100% male, mean age 77 years) with actigraphy and genotype data.Interventions: N/A.Measurements and Results: Common genetic variation in 30 candidate genes was captured using 529 single nucleotide polymorphisms (SNPs). Sleep and activity rhythm traits were objectively measured using wrist actigraphy. In a region of high linkage disequilibrium on chromosome 12p13 containing the candidate gene GNB3, the rs1047776 A allele and the rs2238114 C allele were significantly associated with higher wake after sleep onset (meta-analysis: rs1047776 P-ADD = 2 x 10(-5), rs2238114 P-ADD = 5 x 10(-5)) and lower LRRC23 gene expression (rs1047776:. = -0.22, P = 0.02; rs2238114:. = -0.50, P = 5 x 10(-8)). In MrOS participants, SNPs in ARNTL and NPAS2, genes coding for binding partners, were associated with later sleep and wake onset time (sleep onset time: ARNTL rs3816358 P-2DF = 1 x 10(-4), NPAS2 rs3768984 P-2DF = 5 x 10(-5); wake onset time: rs3816358 P-2DF = 3 x 10(-3), rs3768984 P-2DF = 2 x 10(-4)) and the SNP interaction was significant (sleep onset time P-INT = 0.003, wake onset time P-INT = 0.001). A SNP association in the CLOCK gene replicated in the MrOS cohort, and rs3768984 was associated with sleep duration in a previously reported study. Cluster analysis identified four clusters of genetic associations.Conclusions: These findings support a role for common genetic variation in clock genes in the regulation of inter-related sleep traits in the elderly.