GENETIC VARIANTS IN CIRCADIAN RHYTHM SLEEP DISORDERS

描述（由申请人提供）：提议是UCSD睡眠障碍和遗传学研究人员与图森NHLBI PGA分析基因组学中心的合作。在昼夜节律睡眠障碍（CRSD）中，患者的首选睡眠时间与昼夜节律系统控制的睡眠阶段不同步。CRSD部分源于昼夜节律系统基因的遗传变异。然而，在人类中，对可能产生CRSD易感性的基因的功能序列变异的性质和流行程度知之甚少，也没有对上位性相互作用进行研究。根据Horne-Ostberg量表以及严格的纳入和排除标准，共招募200名夜间型患者。每位患者的表型将通过临床数据、问卷调查和为期2周的手腕活动记录来表征，以客观地确定睡眠时间。然后选择200个对照，按年龄、性别和种族匹配病例。将抽取血样使淋巴母细胞永生以保存DNA。另外还将使用92名斯堪的纳维亚人的样本。从40例晚型患者的DNA中，将确定10个昼夜节律系统基因的外显子和邻近启动子和内含子区域的序列。snp和其他变异将被发现，发表在NCBI dbSNP数据库中，并制成表格。然后对所有200名CRSD患者、200名匹配对照和斯堪的纳维亚样本进行基因分型，以识别CRSD与特定SNP等位基因、单倍型和上位性相互作用的关联。这一建议可能会确定人类昼夜节律系统主要基因中的许多常见变异。此外，更多地了解CRSD的表型和遗传原因将导致CRSD的临床诊断方法，减轻遗传易感性带来的痛苦，并增加对昼夜节律系统的基础科学理解。

DESCRIPTION (provided by applicant): Proposed is a collaboration of UCSD sleep disorders and genetics investigators with the NHLBI PGA Analytical Genomics Center in Tucson. In circadian rhythm sleep disorders (CRSD), the patient's preferred sleeping time is malsynchronized with the sleep phase controlled by the circadian system. The CRSD arise partly from genetic variants in circadian system genes. Nevertheless, in humans, relatively little is known about the nature and prevalence of functional sequence variations in the genes which might produce CRSD susceptibility, nor have epistatic interactions been studied. A total of 200 evening-type patients will be recruited according to the Horne-Ostberg scale plus strict inclusion and exclusion criteria. Each patient's phenotype will be characterized by clinical data, questionnaires, and a 2-week recording of wrist activity to objectively determine sleep timing. Then 200 controls will be selected, matched to cases by age, gender, and ethnicity. Blood samples will be drawn to immortalize lymphoblastoids for DNA preservation. An additional sample of 92 Scandinavian subjects will also be used. From DNA of 40 evening-type patients, the sequences of exons and adjacent promoter and intronic regions will be determined for 10 circadian system genes. SNPs and other variants will be discovered, published in the NCBI dbSNP data base, and tabulated. The variants will then be genotyped in all 200 CRSD patients, 200 matched controls, and the Scandinavian sample, to recognize associations of CRSD with particular SNP alleles, haplotypes, and epistatic interactions. This proposal is likely to identify many of the common variants in the major genes of the human circadian system. Moreover, understanding more about the phenotypes and genetic causes of CRSD will lead to clinical diagnostic methods for CRSD, progress toward alleviating suffering due to genetic susceptibilities, and increased basic science understanding of the circadian system.