Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype.
Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype.
复制标题
DOI：
10.1038/mp.2008.66
复制
发表时间：
2010-02
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管有令人信服的证据表明基因对双相情感障碍的风险有重大贡献，但涉及特定基因或病理生理系统的确凿证据已被证明是难以捉摸的。在某种程度上，这可能与目前表型定义的未知有效性和随后的样本病因异质性有关。在最近的Wellcome Trust Case Control Consortium（WTCCC）双相情感障碍全基因组关联分析（1868例，2938例对照）中，最强关联的多态性之一位于编码GABAA受体β1亚基的基因GABRB 1内。为了增加生物同质性，我们寻找在该多态性处显示最强信号的诊断子集，并使用该子集来测试与GABAA受体基因家族其他成员相关的独立证据。在279例符合双相情感性精神障碍研究诊断标准的病例中，索引信号显著富集（p=3.8×10−6）。独立地，这些病例显示了强有力的证据，GABAA受体基因的变异影响这种表型的风险（独立系统范围p=6.6×10−5），相关信号也位于GABRA 4，GABRB 3，GABRA 5和GABRR 1。我们的研究结果有可能为了解双相情感障碍的表现、发病机制和疾病分类学提供信息。我们的表型细化的方法可能是有用的其他复杂的精神和非精神疾病的研究。
Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium (WTCCC) genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABAA receptor β1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABAA receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (p=3.8×10−6). Independently, these cases showed strong evidence that variation in GABAA receptor genes influences risk for this phenotype (independent system-wide p=6.6×10−5) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR1. Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.
登录
查看更多内容
影响因子：
7
作者：
Hoh, J;Wille, A;Ott, J
通讯作者：
Ott, J
影响因子：
4.4
作者：
Craddock N;Jones I;Kirov G;Jones L
通讯作者：
Jones L
影响因子：
--
作者：
McGuffin, P;Rijsdijk, F;Cardno, A
通讯作者：
Cardno, A
影响因子：
5.8
作者：
Barrett, JC;Fry, B;Daly, MJ
通讯作者：
Daly, MJ
DOI：
10.1007/s00406-005-0583-9
发表时间：
2005-06-01
影响因子：
4.7
作者：
Maier, W;Höfgen, B;Rietschel, M
通讯作者：
Rietschel, M