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.

Effect of rs1063843 in theCAMKK2gene on the dorsolateral prefrontal cortex

“…This SNP, rs1063843, was also found to be significantly associated with SCZ (sample size: 17,154 patients and 113,469 controls) with the T allele that was associated with relatively low expression of CAMKK2 mRNA was more common among SCZ patients. This association has been replicated by a recent, independent study [Atakhorrami et al, ].…”

Functional analysis of an R311C variant of Ca2+‐calmodulin‐dependent protein kinase kinase‐2 (CaMKK2) found as a de novo mutation in a patient with bipolar disorder

“…These detrimental effects identify the R311C variant as the most functionally disruptive among the CaMKK2 loss‐of‐function mutations that have been characterized so far. Notably, the large decrease (> 50%) in CaMKK2 activity displayed by the R311C mutant is similar in magnitude to the reduction in CaMKK2 observed in the dorsolateral prefrontal cortex of bipolar patients 12,26 . Of the three major effects of the R311C mutation, the impairment of T85 autophosphorylation is perhaps the most significant, as the inability to achieve T85 autophosphorylation in response to Ca 2+ ‐CaM activation prevented the R311C mutant from remaining in the activated state after removal of the Ca 2+ ‐signal.…”

“…In this study, we investigated the effects of a de novo R311C mutation in human CaMKK2 that was identified from a trio-family, whole- mutant is similar in magnitude to the reduction in CaMKK2 observed in the dorsolateral prefrontal cortex of bipolar patients. 12,26 Of the three major effects of the R311C mutation, the impairment of T85 autophosphorylation is perhaps the most significant, as the inability to achieve T85 autophosphorylation in response to Ca 2+ -CaM activation prevented the R311C mutant from remaining in the activated state after removal of the Ca 2+ -signal. This is analogous to the effect of the T85S mutation in human CaMKK2, which was shown previously by two independent, candidate gene association studies to display significant links with bipolar and anxiety disorder.…”

The Role of Mitochondria in Mood Disorders: From Physiology to Pathophysiology and to Treatment

“…Through activation of AMP-activated protein kinase (AMPK) and the master mitochondrial regulator, PGC1α, tightly linked to the circadian clock ( 118 ), CaMKK2 regulates mitochondrial function and whole-body energy balance. Bipolar disorder is associated with mutations that affect the function or experssion of CaMKK2 ( 119 ). Decreased CaMKK2 function leads to decreased BDNF expression, a known biomarker of BD.…”