1] College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China [2] Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA.
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
Mol Psychiatry. 2014 Jul;19(7):774-83. doi: 10.1038/mp.2013.103. Epub 2013 Aug 20.
Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
在精神分裂症患者和健康对照者之间差异表达的基因可能在精神分裂症的发病机制中起关键作用。我们分析了两项大规模的全基因组表达研究，这些研究检查了精神分裂症患者及其匹配对照者的基因表达变化。我们发现钙/钙调蛋白（CAM）依赖性蛋白激酶激酶 2（CAMKK2）在这两项研究中的精神分裂症个体中均显著下调。为了寻找可能调节 CAMKK2 表达的潜在遗传变异，我们研究了 CAMKK2 内的单核苷酸多态性（SNP）与 CAMKK2 表达水平之间的关联。我们发现一个 SNP，rs1063843，位于 CAMKK2 的内含子 17 中，与人类大脑（P=1.1×10(-6))和淋巴母细胞系（最低 P=8.4×10(-6))中 CAMKK2 的表达水平强烈相关。我们进一步在多个独立人群（共 130623 名受试者）中研究了 rs1063843 与精神分裂症之间的关联，发现 rs1063843 与精神分裂症显著相关（P=5.17×10(-5))。有趣的是，我们发现与 CAMKK2 表达水平较低相关的 rs1063843 的 T 等位基因在所有测试样本中的精神分裂症个体中出现频率更高，表明 rs1063843 可能是一个因果变异。我们还发现 rs1063843 与人类的认知功能和个性有关。此外，蛋白质-蛋白质相互作用（PPI）分析表明，CAMKK2 参与由顶级精神分裂症基因形成的高度相互关联的 PPI 网络，这进一步支持了 CAMKK2 在精神分裂症发病机制中的潜在作用。综上所述，这些相互一致的证据强烈表明，CAMKK2 可能在精神分裂症易感性中起关键作用。
