The genetics of bipolar disorder.
The genetics of bipolar disorder.
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DOI：
10.1016/j.neuroscience.2009.03.080
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发表时间：
2009-11-24
期刊：
影响因子：
3.3
通讯作者：
Smoller, J. W.
中科院分区：
文献类型：
--
作者：
Barnett, J. H.;Smoller, J. W.
双相情感障碍是一种以躁狂症和抑郁症发作为特征的情绪障碍。双胞胎研究已经确定双相情感障碍是最具遗传性的医学障碍之一，在过去的二十年中，识别特定易感基因的努力已经加强。由于缺乏动物模型，对发病机制的了解有限，以及该综合征的遗传和表型复杂性，寻找影响双相情感障碍的基因变得复杂。连锁研究暗示了一些染色体区域作为窝藏相关基因，但结果一直不一致。现在人们普遍认为，双相情感障碍的遗传倾向反映了许多单独影响较小的基因的作用，这种情况不适合连锁研究。因此，对适度效应位点检测更为有效的关联研究成为基因发现研究的热点。大量的候选基因，包括来自疾病发病机制假设的生物学候选基因和来自连锁和细胞遗传学研究的位置候选基因，已经被评估。在独立研究中，这些基因中有几个与该疾病相关（包括BDNF、DAOA、DISC1、GRIK4、SLC6A4和TPH2），但没有一个得到证实。双相情感障碍的临床异质性及其与其他疾病（特别是精神分裂症、分裂情感障碍和重度抑郁症）的表型和遗传重叠引起了对遗传研究的最佳表型定义的质疑。尽管如此，全基因组关联分析已经成功地确定了多种复杂疾病的易感基因，并开始涉及双相情感障碍的特定基因（DGKH, CACNA1C, ANK3）。这种疾病的多基因性意味着需要非常大的样本来检测可能导致双相情感障碍的适度影响位点。详细的基因解剖可能为干预提供新的靶点（药理学和社会心理）。
Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) has raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.
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