Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety
Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety
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DOI：
10.1038/mp.2008.143
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发表时间：
2009-07-01
影响因子：
11
通讯作者：
Williams, L. M.
中科院分区：
文献类型：
--
作者：
Gatt, J. M.;Nemeroff, C. B.;Williams, L. M.
抑郁症和焦虑症的个体风险标记已被确定，但将基因和环境与这些标记联系起来的明确途径仍然未知。在这里，我们检查了 374 名健康欧洲志愿者的抑郁和焦虑症状，研究了脑源性神经营养因子 (BDNF) Val66Met 基因与早期生活压力 (ELS) 暴露在大脑（杏仁核 - 海马前额叶灰质体积）、身体（心率）、气质和认知之间的显性相互作用。脑成像数据基于 89 名参与者的子集。多元回归分析揭示了 ELS 对身体唤醒（静息心率，P = 0.005）和症状（抑郁和焦虑，P < 0.001）的主要影响，而 BDNF 没有主要影响。此外，显着的 BDNF -ELS 相互作用表明，暴露于较高 ELS 的 BDNF Met 携带者的海马和杏仁核体积较小（P = 0.013）、心率升高（P = 0.0002）和工作记忆下降（P = 0.022）。结构方程路径模型用于确定这种相互作用是否通过调节对大脑、身体和认知测量的影响来预测焦虑和抑郁。 Met携带者状态和暴露于ELS的组合预测海马灰质减少(P < 0.001)，以及相关的外侧前额皮质(P < 0.001)，进而导致更高的抑郁症(P = 0.005)。抑郁程度越高，工作记忆能力越差（P = 0.005），反应速度也越慢。 BDNF Met -ELS 相互作用还通过身体唤醒的增加预测神经质的增加以及抑郁和焦虑的增加（P < 0.001）。相反，BDNF V/ V 基因型和 ELS 的组合预测杏仁核灰质 (P = 0.003) 和相关内侧前额叶皮层 (P < 0.001) 的增加，进而预测惊吓引起的心率变异性 (P = 0.026) 和更高的焦虑 (P = 0.026)。较高的焦虑程度与言语记忆和冲动有关。这些影响是 BDNF 基因特有的，对于相关的 5HTT-LPR 多态性并不明显。总体而言，这些发现与抑郁和焦虑的相关性一致，但表明即使在非临床样本中，也可以识别这些综合征的部分分化基因-大脑认知途径。这些发现可能有助于为更有针对性的干预策略建立证据基础。分子精神病学 (2009) 14, 681-695; doi：10.1038/mp.2008.143； 2009 年 1 月 20 日在线发布
Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala -hippocampal prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P = 0.005) and symptoms (depression and anxiety, P < 0.001) in the absence of main effects for BDNF. In addition, significant BDNF -ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P = 0.013), heart rate elevations (P = 0.0002) and a decline in working memory (P = 0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P < 0.001), and associated lateral prefrontal cortex (P< 0.001) and, in turn, higher depression (P = 0.005). Higher depression was associated with poorer working memory (P = 0.005), and slowed response speed. The BDNF Met -ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P < 0.001). In contrast, the combination of BDNF V/ V genotype and ELS predicted increases in gray matter of the amygdala (P = 0.003) and associated medial prefrontal cortex (P< 0.001), which in turn predicted startle-elicited heart rate variability (P= 0.026) and higher anxiety (P = 0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene -brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies. Molecular Psychiatry (2009) 14, 681-695; doi:10.1038/mp.2008.143; published online 20 January 2009