Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
Am J Psychiatry. 2012 Sep;169(9):982-90. doi: 10.1176/appi.ajp.2012.11101585.
Genome-wide association has been reported between the NCAN gene and bipolar disorder. The aims of this study were to characterize the clinical symptomatology most strongly influenced by NCAN and to explore the behavioral phenotype of Ncan knockout (Ncan(-/-)) mice.
Genotype/phenotype correlations were investigated in patients with bipolar disorder (N=641) and the genetically related disorders major depression (N=597) and schizophrenia (N=480). Principal components and genotype association analyses were used to derive main clinical factors from 69 lifetime symptoms and to determine which of these factors were associated with the NCAN risk allele. These analyses were then repeated using the associated factor(s) only in order to identify the more specific clinical subdimensions that drive the association. Ncan(-/-) mice were tested using diverse paradigms, assessing a range of behavioral traits, including paradigms corresponding to bipolar symptoms in humans.
In the combined patient sample, the NCAN risk allele was significantly associated with the "mania" factor, in particular the subdimension "overactivity." Ncan(-/-) mice were hyperactive and showed more frequent risk-taking and repetitive behaviors, less depression-like conduct, impaired prepulse inhibition, amphetamine hypersensitivity, and increased saccharin preference. These aberrant behavioral responses normalized after the administration of lithium.
NCAN preferentially affected mania symptoms in humans. Ncan(-/-) mice showed behavioral abnormalities that were strikingly similar to those of the human mania phenotype and may thus serve as a valid mouse model.
全基因组关联已报道 NCAN 基因与双相情感障碍之间存在关联。本研究旨在描述受 NCAN 影响最大的临床症状，并探索 Ncan 敲除（Ncan(-/-)）小鼠的行为表型。
在双相情感障碍患者（N=641）、遗传相关疾病重度抑郁症（N=597）和精神分裂症（N=480）患者中进行基因型/表型相关性研究。使用主成分和基因型关联分析，从 69 项终生症状中得出主要临床因素，并确定哪些因素与 NCAN 风险等位基因相关。然后仅使用相关因素重复这些分析，以确定驱动关联的更具体的临床亚维度。使用多种范式对 Ncan(-/-) 小鼠进行测试，评估一系列行为特征，包括与人类双相症状相对应的范式。
在合并的患者样本中，NCAN 风险等位基因与“躁狂”因子显著相关，特别是“过度活动”的亚维度。Ncan(-/-) 小鼠表现出过度活跃，表现出更多的冒险和重复行为，较少的抑郁样行为，损害的前脉冲抑制，安非他命敏感性增加，以及增加的蔗糖偏好。这些异常的行为反应在给予锂后恢复正常。
NCAN 优先影响人类的躁狂症状。Ncan(-/-) 小鼠表现出与人类躁狂表型非常相似的行为异常，因此可能作为一种有效的小鼠模型。
