Kalmbach David A, Schneider Logan D, Cheung Joseph, Bertrand Sarah J, Kariharan Thiruchelvam, Pack Allan I, Gehrman Philip R
Departments of Psychiatry and Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94063.
Sleep. 2017 Feb 1;40(2). doi: 10.1093/sleep/zsw048.
Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related illnesses. Family studies indicate that chronotype is a heritable trait, thus directing attention toward its genetic basis. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWAS), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. This review discusses the findings of these landmark GWASs in the context of prior research.
We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype.
A good deal of consistency was observed across studies with 9 genes identified in 2 of the 3 GWASs. Several genes previously unknown to influence chronotype were identified.
GWAS is an important tool in identifying common variants associated with the complex chronotype phenotype, the findings of which can supplement and guide molecular science. Future directions in model systems and discovery of rare variants are discussed.
昼夜节律类型，即昼夜偏好，指的是内源性昼夜节律系统的行为表现，该系统控制着睡眠和觉醒的偏好时间。由于昼夜节律时间的变化和系统紊乱与疾病发展相关，昼夜节律类型的基础生物学因其在睡眠及相关疾病的调节和失调中的作用而受到关注。家族研究表明昼夜节律类型是一种可遗传的特征，因此将注意力引向了其遗传基础。尽管对候选基因的分子研究发现为其遗传结构提供了线索，但基因变异对昼夜节律类型的贡献仍不明确，仅鉴定出少数相关变异。随着大规模全基因组关联研究（GWAS）的出现，科学家现在有能力发现与复杂表型相关的新的常见基因变异。最近对来自23andMe队列和英国生物银行的欧洲血统受试者进行了三项大规模的昼夜节律类型GWAS研究。本综述在先前研究的背景下讨论了这些具有里程碑意义的GWAS研究的结果。
我们系统地回顾和比较了三项昼夜节律类型GWAS研究的方法、分析方法和结果。
各项研究之间观察到了大量的一致性，在三项GWAS研究中的两项中鉴定出了9个基因。还鉴定出了几个以前未知会影响昼夜节律类型的基因。
GWAS是识别与复杂的昼夜节律类型表型相关的常见变异的重要工具，其研究结果可以补充和指导分子科学。文中还讨论了模型系统的未来方向以及罕见变异的发现。
