Lohoff F W, Hodge R, Narasimhan S, Nall A, Ferraro T N, Mickey B J, Heitzeg M M, Langenecker S A, Zubieta J-K, Bogdan R, Nikolova Y S, Drabant E, Hariri A R, Bevilacqua L, Goldman D, Doyle G A
Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
Mol Psychiatry. 2014 Jan;19(1):129-39. doi: 10.1038/mp.2012.193. Epub 2013 Jan 22.
Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.
情绪行为部分具有遗传性，且在精神病理学中常常受到干扰。确定驱动这种遗传性的特定基因变异可能会为涉及情绪的分子和神经生物学机制提供重要的新见解。我们的结果表明，突触前囊泡单胺转运体1（VMAT1）的苏氨酸136异亮氨酸（rs1390938）多态性在体外具有功能，异亮氨酸等位基因导致单胺向突触前囊泡的转运增加。此外，我们表明，苏氨酸136异亮氨酸变异体在情绪脑回路中预测了不同的反应，这与其在体外的作用一致。最后，对双相情感障碍（BPD）患者和对照组的深度测序确定了几个罕见的新型VMAT1变异体。变异体苯丙氨酸84丝氨酸仅存在于BPD个体中，并导致体外单胺转运显著增加。综上所述，我们的数据表明，VMAT1多态性影响单胺信号传导、情绪脑回路的功能反应以及精神病理学风险。
