| 1 | Mol. Psychiatry 2014 Jul 19: 774-83 |
|---|---|
| PMID | 23958956 |
| Title | Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene. |
| Abstract | Genes that are differentially expressed betweenschizophreniapatients and healthy controls may have key roles in the pathogenesis ofschizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression inschizophreniapatients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals withschizophreniain both studies. To seek the potential genetic variants that may regulate the expression ofCAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) withinCAMKK2and the expression level ofCAMKK2. We found one SNP, rs1063843, which is located in intron 17 ofCAMKK2, is strongly associated with the expression level ofCAMKK2in 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 andschizophreniain multiple independent populations (a total of 130?623 subjects) and found rs1063843 is significantly associated withschizophrenia(P=5.17 � 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level ofCAMKK2, has a higher frequency in individuals withschizophreniain 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 thatCAMKK2participates in a highly interconnected PPI network formed by topschizophreniagenes, which further supports the potential role ofCAMKK2in the pathogenesis ofschizophrenia. Taken together, these converging lines of evidence strongly suggest thatCAMKK2may have pivotal roles inschizophreniasusceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Sci Rep 2015 -1 5: 14436 |
| PMID | 26395653 |
| Title | Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. |
| Abstract | Mutations that reduce expression or give rise to a Thr85Ser (T85S) mutation of Ca(2+)-CaM-dependent protein kinase kinase-2 (CAMKK2) have been implicated in behavioural disorders such as anxiety, bipolar andschizophreniain humans. Here we report that Thr85 is an autophosphorylation site that endowsCAMKK2with a molecular memory that enables sustained autonomous activation following an initial, transient Ca(2+) signal. Conversely, autophosphorylation of Ser85 in the T85S mutant fails to generate autonomous activity but instead causes a partial loss ofCAMKK2activity. The loss of autonomous activity in the mutant can be rescued by blocking glycogen synthase kinase-3 (GSK3) phosphorylation ofCAMKK2with the anti-mania drug lithium. Furthermore,CAMKK2null mice representing a loss of function model the human behavioural phenotypes, displaying anxiety and manic-like behavioural disturbances. Our data provide a novel insight intoCAMKK2regulation and its perturbation by a mutation associated with behavioural disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J Neural Transm (Vienna) 2016 Mar 123: 323-8 |
| PMID | 26354101 |
| Title | A genetic variant in CAMKK2 gene is possibly associated with increased risk of bipolar disorder. |
| Abstract | 最近的一项大型研究报道at rs1063843, a single nucleotide polymorphism located in theCAMKK2gene is highly associated withschizophreniain European and Han Chinese populations. Increasing evidences show thatschizophreniaand bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant withschizophreniaand bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500schizophrenicpatients, 500 bipolar patients and 500 normal controls and all were genotyped for the rs1063843 using a PCR-RFLP method. The allele frequency of rs1063843 was significantly different in bothschizophreniaand bipolar patients comparing to control group. For the first time, we showed that rs1063843 is highly associated with bipolar disorder, although more replication studies are needed to confirm our findings. Our results also support the findings of previous studies suggesting a significant association between rs1063843 andschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J Neural Transm (Vienna) 2016 Mar 123: 323-8 |
| PMID | 26354101 |
| Title | A genetic variant in CAMKK2 gene is possibly associated with increased risk of bipolar disorder. |
| Abstract | 最近的一项大型研究报道at rs1063843, a single nucleotide polymorphism located in theCAMKK2gene is highly associated withschizophreniain European and Han Chinese populations. Increasing evidences show thatschizophreniaand bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant withschizophreniaand bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500schizophrenicpatients, 500 bipolar patients and 500 normal controls and all were genotyped for the rs1063843 using a PCR-RFLP method. The allele frequency of rs1063843 was significantly different in bothschizophreniaand bipolar patients comparing to control group. For the first time, we showed that rs1063843 is highly associated with bipolar disorder, although more replication studies are needed to confirm our findings. Our results also support the findings of previous studies suggesting a significant association between rs1063843 andschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Hum Brain Mapp 2016 Mar -1: -1 |
| PMID | 27004598 |
| Title | Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex. |
| Abstract | Recently, a single nucleotide polymorphism (SNP) in theCAMKK2gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and withschizophrenia(SCZ)和赤字在工作记忆和执行function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N?=?84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N-back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed. Across all three tasks, it was found that carriers of the risk allele consistently exhibited increased activation of the left DLPFC. In addition, the risk allele carriers also exhibited increased activation of the right DLPFC and the left cerebellum during the Stroop task and of the left caudate nucleus during the N-back task. These findings helped to elucidate the role ofCAMKK2in cognitive functions and in the etiology of SCZ. Hum Brain Mapp, 2016. � 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic |