Expanding the phenotype half of the genotype-phenotype space.
Expanding the phenotype half of the genotype-phenotype space.
复制标题
扩大基因型-表型空间的表型一半。
DOI：
10.1073/pnas.1525363113
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发表时间：
2016
影响因子：
11.1
通讯作者：
Bućan,Maja
中科院分区：
文献类型：
--
作者：
Bućan,Maja
双相情感障碍（BP），也称为躁狂抑郁症，是一种大脑疾病，会导致情绪，能量和活动水平的异常变化（1）。BP的一些最突出和特征性的症状包括睡眠中的戏剧性干扰：觉醒或休息：活动周期，在躁狂阶段的躁动和抑郁阶段的活动水平极低（“难以起床”）（2，3）。另外，休息：活动周期可以深刻地改变临床表现的过程;通常用于治疗这种疾病的药物，如锂和抗抑郁药，显著改变了情感发作在疾病纵向过程中的周期（2，3）。在PNAS中，帕加尼等人（2005）在PNAS中，(4)报告，据他们所知，第一次大规模的系统分析休息：活动表型在26个家系分离的严重BP。这项研究涉及监测两个星期的活动，在136个正常的（躁狂症或抑郁症发作之间）BP主题和422个非BP亲属。为了确定睡眠，活动和昼夜节律表型与显着的遗传成分，作者估计遗传力。简而言之，他们比较了家族关系的程度与所有家庭成员收集的73种表型的相似程度。除了确定可遗传的休息：活动性状，该分析还确定了与疾病状态相关的表型子集。如帕加尼等人的论文（4）所述，系统描述遗传性疾病相关性状对于将基因组病变（如通过下一代测序鉴定的病变）与复杂精神疾病联系起来的持续努力至关重要。20多年前，在哥斯达黎加和哥伦比亚安蒂奥基亚的中央谷的几个多代家系中开始了BP的遗传学研究，目的是确定与整体综合征相关的“主基因”（5-8）。这一信息是响亮而明确的：即使在遗传隔离人群的家庭中，在没有高影响风险等位基因的不同家庭中，BP的遗传基础也存在显着差异。一个国际合作小组，其中包括来自哥斯达黎加和哥伦比亚的临床医生和科学家，开始了一个雄心勃勃的项目，以测量范围广泛的数量性状在正常的BP科目和他们的非BP家庭成员。除了临床评估，以及睡眠，活动和昼夜节律的测量外（4），他们还评估了来自神经认知电池和神经成像的169个特征的家族聚集（9，10）。使用复杂的统计方法，恐惧等。(9)确定了126个显著遗传的，53个与严重BP（BP-I）相关。与BP相关的可遗传表型包括妄想倾向、知觉创造力和
Bipolar disorder (BP), also known as manic-depressive illness, is a brain disorder that causes unusual shifts in mood, energy, and activity levels (1). Some of the most prominent and characteristic symptoms of BP include dramatic disturbances in sleep: wake or rest: activity cycles, with restlessness in the manic phase and extremely low levels of activity during the depressive phase (“having difficulty getting out of bed”)(2, 3). Also, rest: activity cycles can profoundly change the course of clinical manifestations; pharmacological agents such as lithium and antidepressants, which are commonly used to treat this illness, significantly alter the cycling of affective episodes over the longitudinal course of the disorder (2, 3). In PNAS, Pagani et al.(4) report, to their knowledge, the first largescale systematic analysis of rest: activity phenotypes in 26 pedigrees segregating for severe BP. This study involved monitoring of actigraphy for two weeks in 136 euthymic (between episodes of mania or depression) BP subjects and 422 of their non-BP relatives. To identify sleep, activity, and circadian rhythm phenotypes with a significant genetic component, the authors estimated heritability. In simple terms, they compared the degree of familial relationships with the level of similarity in 73 phenotypes collected for all family members. In addition to identifying heritable rest: activity traits, this analysis also identified a subset of phenotypes correlated with the disease status. Systematic delineation of heritable disease-associated traits, as illustrated in the Pagani et al. paper (4), will be critical in ongoing efforts to link genomic lesions—such as those identified by next-generation sequencing—to complex psychiatric disorders. Genetic investigations of BP in several multigenerational pedigrees from the Central Valley of Costa Rica and Antioquia in Colombia started more than 20 y ago with classical linkage studies aimed at identifying “major genes” linked to the overall syndrome (5–8). The message was loud and clear: Even in families from genetically isolated populations, there was significant variation in the genetic basis for BP in different families with no high-impact risk alleles. An international collaborative team, which included clinicians and scientists from Costa Rica and Colombia, embarked on an ambitious project to measure a wide range of quantitative traits in euthymic BP subjects and their non-BP family members. In addition to clinical assessments, and measurements of sleep, activity, and circadian rhythms (4), they also assessed the familial aggregation of 169 traits from neurocognitive batteries and neuroimaging (9, 10). Using sophisticated statistical methodology, Fears et al.(9) identified 126 significantly heritable and 53 were associated with severe BP (BP-I). Among phenotypes that are heritable and associated with BP are proneness to delusions, perceptual creativity, and