| 1 | Mol. Psychiatry 2014 Jul 19: 774-83 |
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| PMID | 23958956 |
| Title | Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Sci Rep 2015 -1 5: 14436 |
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| 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 and schizophrenia in humans. Here we report that Thr85 is an autophosphorylation site that endows CAMKK2 with 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 of CAMKK2 activity. The loss of autonomous activity in the mutant can be rescued by blocking glycogen synthase kinase-3 (GSK3) phosphorylation of CAMKK2 with the anti-mania drug lithium. Furthermore, CAMKK2 null mice representing a loss of function model the human behavioural phenotypes, displaying anxiety and manic-like behavioural disturbances. Our data provide a novel insight into CAMKK2 regulation and its perturbation by a mutation associated with behavioural disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J Neural Transm (Vienna) 2016 Mar 123: 323-8 |
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| PMID | 26354101 |
| Title | A genetic variant in CAMKK2 gene is possibly associated with increased risk of bipolar disorder. |
| Abstract | A recent large-scale study have reported that rs1063843, a single nucleotide polymorphism located in the CAMKK2 gene is highly associated with schizophrenia in European and Han Chinese populations. Increasing evidences show that schizophrenia and bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant with schizophrenia and bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500 schizophrenic patients, 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 both schizophrenia and 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 and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J Neural Transm (Vienna) 2016 Mar 123: 323-8 |
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| PMID | 26354101 |
| Title | A genetic variant in CAMKK2 gene is possibly associated with increased risk of bipolar disorder. |
| Abstract | A recent large-scale study have reported that rs1063843, a single nucleotide polymorphism located in the CAMKK2 gene is highly associated with schizophrenia in European and Han Chinese populations. Increasing evidences show that schizophrenia and bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant with schizophrenia and bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500 schizophrenic patients, 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 both schizophrenia and 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 and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Hum Brain Mapp 2016 Mar -1: -1 |
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| PMID | 27004598 |
| Title | Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex. |
| Abstract | Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive 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 of CAMKK2 in cognitive functions and in the etiology of SCZ. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic |