McCarthy Michael J
Department of Psychiatry, Center for Circadian Biology, VA San Diego Healthcare System, University of California San Diego, San Diego, California, USA.
Psychiatr Genet. 2019 Apr;29(2):29-36. doi: 10.1097/YPG.0000000000000215.
Circadian rhythm abnormalities have been recognized as a central feature of bipolar disorder (BD) but a coherent biological explanation for them remains lacking. Using genetic mutation of 'clock genes', robust animal models of mania and depression have been developed that elucidate key aspects of circadian rhythms and the circadian clock-mood connection. However, translation of this knowledge into humans remains incomplete. In recent years, very large genome-wide association studies (GWAS) have been conducted and the genetic underpinnings of BD are beginning to emerge. However, these genetic studies in BD do not match well with the evidence from animal studies that implicate the circadian clock in mood regulation. Even larger GWAS have been conducted for circadian phenotypes including chronotype, rhythm amplitude, sleep duration, and insomnia. These studies have identified a diverse set of associated genes, including a minority with previously well-characterized functions in the circadian clock. Taken together, the data from recent GWAS of BD and circadian phenotypes indicate that the genetic organization of the circadian clock, both in health and in BD is complex. The findings from GWAS elucidate potentially novel circadian mechanism that may be partly distinct from those identified in animal models. Pleiotropy, epistasis and nongenetic factors may play important roles in regulating circadian rhythms, some of which may underlie circadian rhythm disturbances in BD.
昼夜节律异常已被认为是双相情感障碍（BD）的一个核心特征，但对其仍缺乏连贯的生物学解释。通过“生物钟基因”的基因突变，已经建立了强大的躁狂和抑郁动物模型，这些模型阐明了昼夜节律和昼夜生物钟与情绪联系的关键方面。然而，将这些知识转化到人类研究中仍不完整。近年来，已经开展了非常大规模的全基因组关联研究（GWAS），BD的遗传基础正开始显现。然而，BD的这些遗传研究与动物研究中表明昼夜生物钟参与情绪调节的证据不太相符。针对昼夜表型，包括昼夜类型、节律幅度、睡眠时间和失眠，已经开展了更大规模的GWAS。这些研究已经确定了一系列不同的相关基因，其中少数基因在昼夜生物钟中具有先前已充分描述的功能。综合来看，BD和昼夜表型的近期GWAS数据表明，无论是在健康状态还是在BD中，昼夜生物钟的遗传结构都很复杂。GWAS的研究结果阐明了潜在的新昼夜节律机制，这些机制可能部分不同于在动物模型中确定的机制。基因多效性、上位性和非遗传因素可能在调节昼夜节律中起重要作用，其中一些可能是BD中昼夜节律紊乱的基础。
