Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, North Carolina.
Cardiothoracic Division, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
Biol Psychiatry. 2018 Jul 15;84(2):148-159. doi: 10.1016/j.biopsych.2017.11.010. Epub 2017 Nov 16.
Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk.
We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 ± 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available.
Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons.
We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings.
如果不是所有科学学科，那么至少在大多数科学学科中，低复制率都是一个令人担忧的问题。具体在精神遗传学中，针对与潜在遗传效应更密切相关的中间脑表型，被吹捧为一种能够提高效力和可重复性的策略。在当前的研究中，我们试图复制先前发表的单核苷酸多态性与威胁相关的杏仁核反应之间的关联，这是一种不仅与多种疾病的病理生理学有关，而且还被用作未来风险生物标志物的强大脑表型。
我们对发表的单核苷酸多态性与威胁相关的杏仁核反应之间的关联进行了文献检索，发现了 37 个独特的发现。我们的复制样本包括 1117 名年轻成年志愿者（629 名女性，平均年龄 19.72±1.25 岁），他们都有遗传和功能磁共振成像数据。
在所确定的 37 个独特关联中，只有 3 个与之前的报道一致。当与原始发现相比，采用不同的模型参数进行探索性分析时，28 项额外的研究发现了显著的关联：其中 8 项是针对不同的对比/侧别；5 项是针对不同的性别和/或种族/民族；15 项则相反，针对不同的对比、侧别、性别和/或种族/民族。无论模型参数如何，6 项研究均未检测到显著关联。值得注意的是，没有任何显著关联在多重比较校正后仍然显著。
我们讨论了这些复制效果不佳的模式，涉及到在遗传关联研究中针对中间脑表型的一般策略，以及提高影像学遗传学发现的可重复性的重要性日益增加。
