Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder
Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder
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DOI：
10.1038/mp.2008.24
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发表时间：
2009-09-01
影响因子：
11
通讯作者：
Muir, W. J.
中科院分区：
文献类型：
--
作者：
Pickard, B. S.;Christoforou, A.;Muir, W. J.
神经元PAS结构域3（NPAS 3）基因编码神经元转录因子，其通过鉴定与精神分裂症相关的人染色体易位和具有行为和海马神经发生缺陷的小鼠敲除模型而与精神疾病有关。为了确定其对一般人群中精神疾病风险的贡献，我们对368名双相情感障碍患者、386名精神分裂症患者和455名对照者的NPAS 3基因的70个单核苷酸多态性进行了基因分型。中度显着的单标记和全球和个人的单倍型被确定在四个离散区域的基因。在这四个区域中的每一个区域都存在风险和保护性单倍型，表明NPAS 3内的基因座和等位基因异质性，并提出了一种模型，即跨基因的变体之间的相互作用可能有助于对疾病的易感性。这通过预测每个个体在每个相关区域的最可能的单倍型，然后计算NPAS 3介导的“净遗传负荷”值来支持。该值与双相情感障碍（P = 0.0000010）和精神分裂症（P = 0.0000012）的对照组有显著差异。Logistic回归分析也证实了四个相关区域对疾病风险的组合作用。此外，敏感性/特异性图显示，极端的遗传负荷分布具有最大的预测能力，一个功能，表明倍增等位基因相互作用。这些数据增加了最近的证据表明，一些相对较小的效应大小单倍型的组合分析可能有显着的权力来预测一个人的风险复杂的遗传疾病，如精神疾病。Molecular Psychiatry（2009）14，874-884; doi：10.1038/mp.2008.24; 2008年3月4日在线发表
The neuronal PAS domain 3 (NPAS3) gene encodes a neuronal transcription factor that is implicated in psychiatric disorders by the identification of a human chromosomal translocation associated with schizophrenia and a mouse knockout model with behavioural and hippocampal neurogenesis defects. To determine its contribution to the risk of psychiatric illness in the general population, we genotyped 70 single-nucleotide polymorphisms across the NPAS3 gene in 368 individuals with bipolar disorder, 386 individuals with schizophrenia and 455 controls. Modestly significant single-marker and global and individual haplotypes were identified in four discrete regions of the gene. The presence of both risk and protective haplotypes at each of these four regions indicated locus and allelic heterogeneity within NPAS3 and suggested a model whereby interactions between variants across the gene might contribute to susceptibility to illness. This was supported by predicting the most likely haplotype for each individual at each associated region and then calculating an NPAS3-mediated 'net genetic load' value. This value differed significantly from controls for both bipolar disorder (P = 0.0000010) and schizophrenia (P = 0.0000012). Logistic regression analysis also confirmed the combinatorial action of the four associated regions on disease risk. In addition, sensitivity/specificity plots showed that the extremes of the genetic loading distribution possess the greatest predictive power-a feature suggesting multiplicative allele interaction. These data add to recent evidence that the combinatorial analysis of a number of relatively small effect size haplotypes may have significant power to predict an individual's risk of a complex genetic disorder such as psychiatric illness. Molecular Psychiatry (2009) 14, 874-884; doi: 10.1038/mp.2008.24; published online 4 March 2008