GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, London, UK.
Neuroimage. 2010 Nov 15;53(3):908-17. doi: 10.1016/j.neuroimage.2010.02.065. Epub 2010 Feb 26.
Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3beta) in mood disorders. We recently reported associations between GSK3beta polymorphisms and brain structural changes in patients with recurrent major depressive disorder (MDD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3beta biological functions are associated with similar regional grey matter (GM) volume changes in MDD patients. We tested specifically for associations with genetic variation in canonical Wnt signaling pathway genes and in genes that encode substrate proteins of GSK3beta. We applied a general linear model with non-stationary cluster-based inference to examine associations between polymorphisms and regional voxel-based morphometry GM volume differences in recurrent MDD patients (n=134) and in age-, gender-, and ethnicity-matched healthy controls (n=144) to test for genotype-by-MDD interactions. We observed associations for polymorphisms in 8/13 canonical Wnt pathway genes and 5/10 GSK3beta substrate genes, predominantly in the temporolateral and medial prefrontal cortices. Similar associations were not found for 100 unrelated polymorphisms tested. This work suggests that identifying SNPs related to genes that encode functionally-interacting proteins that modulate common anatomical regions offers a useful approach to increasing confidence in outcomes from imaging genetics association studies. This is of particular interest when replication datasets are not available. Our observations lend support to the hypothesis that polymorphisms in GSK3beta play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.
有几条证据表明糖原合成酶激酶 3β（GSK3β）与情绪障碍有关。我们最近报道了 GSK3β 多态性与复发性重度抑郁症（MDD）患者大脑结构变化之间的关联。在这里，我们提供了支持性观察结果，表明与 GSK3β 生物学功能直接相关的编码蛋白的其他基因中的多态性与 MDD 患者的相似区域灰质（GM）体积变化有关。我们专门测试了与经典 Wnt 信号通路基因和编码 GSK3β 底物蛋白的基因中的遗传变异相关的情况。我们应用具有非平稳聚类推理的一般线性模型来检查复发性 MDD 患者（n=134）和年龄、性别和种族匹配的健康对照者（n=144）中多态性与基于体素的形态计量 GM 体积差异之间的关联，以测试基因型与 MDD 的相互作用。我们观察到 13 个经典 Wnt 通路基因中的 8 个和 10 个 GSK3β 底物基因中的 5 个多态性与颞侧和内侧前额叶皮质的关联。在测试的 100 个无关多态性中没有发现类似的关联。这项工作表明，鉴定与编码功能相互作用蛋白的基因相关的 SNPs，这些蛋白可以调节常见的解剖区域，为增加影像学遗传学关联研究结果的可信度提供了一种有用的方法。当没有复制数据集时，这一点尤其重要。我们的观察结果支持这样一种假设，即 GSK3β 中的多态性通过经典 Wnt 信号通路和相关底物发挥作用，部分参与了 MDD 的易感性或表达。
