The NIMH Research Domain Criteria (RDoC) initiative aims to describe key dimensional constructs underlying mental function across multiple units of analysis-from genes to observable behaviors-in order to better understand psychopathology. The acute threat ("fear") construct of the RDoC Negative Valence System has been studied extensively from a translational perspective, and is highly pertinent to numerous psychiatric conditions, including anxiety and trauma-related disorders. We examined genetic contributions to the construct of acute threat at two units of analysis within the RDoC framework: (1) neural circuits and (2) physiology. Specifically, we focused on genetic influences on activation patterns of frontolimbic neural circuitry and on startle, skin conductance, and heart rate responses. Research on the heritability of activation in threat-related frontolimbic neural circuitry is lacking, but physiological indicators of acute threat have been found to be moderately heritable (35-50%). Genetic studies of the neural circuitry and physiology of acute threat have almost exclusively relied on the candidate gene method and, as in the broader psychiatric genetics literature, most findings have failed to replicate. The most robust support has been demonstrated for associations between variation in the serotonin transporter (SLC6A4) and catechol-O-methyltransferase (COMT) genes with threat-related neural activation and physiological responses. However, unbiased genome-wide approaches using very large samples are needed for gene discovery, and these can be accomplished with collaborative consortium-based research efforts, such as those of the Psychiatric Genomics Consortium (PGC) and Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium.

译文

NIMH研究领域标准 (RDoC) 计划旨在描述跨多个分析单位 (从基因到可观察到的行为) 的心理功能的关键维度构建,以便更好地了解心理病理学。RDoC负价系统的急性威胁 (“恐惧”) 结构已从翻译的角度进行了广泛研究,并且与许多精神疾病 (包括焦虑和创伤相关疾病) 高度相关。我们在RDoC框架内的两个分析单位检查了对急性威胁构建的遗传贡献 :( 1) 神经回路和 (2) 生理学。具体来说,我们专注于遗传对额边缘神经回路激活模式以及惊吓,皮肤电导和心率反应的影响。缺乏对威胁相关的额边缘神经回路中激活的遗传力的研究,但已发现急性威胁的生理指标具有中等遗传性 (35-50%)。对急性威胁的神经回路和生理学的遗传研究几乎完全依赖于候选基因方法,并且与更广泛的精神病学遗传学文献一样,大多数发现都无法复制。5-羟色胺转运蛋白 (SLC6A4) 和儿茶酚-O-甲基转移酶 (COMT) 基因的变异与威胁相关的神经激活和生理反应之间的关联已得到最有力的支持。然而,基因发现需要使用非常大样本的无偏全基因组方法,这些方法可以通过基于合作联盟的研究工作来实现,例如精神病学基因组学联盟 (PGC) 的研究工作,并通过荟萃分析 (ENIGMA) 联盟来增强神经成像遗传学。

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