The Gender-Specific Interaction of DVL3 and GSK3β Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study

Abstract

Based on the “oxidative stress hypothesis” of major depressive disorder (MDD), cells regulate their structure through the Wnt pathway. Little is known regarding the interactions of dishevelled 3 (DVL3) and glycogen synthase kinase 3 beta (GSK3β) polymorphisms with MDD. The aim of the current study was to verify the relationship between DVL3 and GSK3β genetic variants in a Chinese Han population and further to evaluate whether these interactions exhibit gender-specificity. A total of 1136 participants, consisting of 541 MDD patients and 595 healthy subjects, were recruited. Five single-nucleotide polymorphisms (SNPs) of DVL3/GSK3β were selected to assess their interaction by use of a generalized multifactor dimensionality reduction method. The genotype and haplotype frequencies of DVL3/GSK3β polymorphisms were significantly different between patients and controls for DVL3 rs1709642 ( P < 0.01 ) and GSK3β rs334558, rs6438552, and rs2199503 ( P < 0.01 ). In addition, our results also showed that there were significant interaction effects between DVL3 and GSK3β polymorphisms and the risk of developing MDD, particularly in women. The interaction between DVL3 (rs1709642) and GSK3β (rs334558, rs6438552) showed a cross-validation (CV) consistency of 10/10, a P value of 0.001, and a testing accuracy of 59.22%, which was considered as the best generalized multifactor dimensionality reduction (GMDR) model. This study reveals the interaction between DVL3 and GSK3β polymorphisms on MDD susceptibility in a female Chinese Han population. The effect of gender should be taken into account in future studies that seek to explore the genetic predisposition to MDD relative to the DVL3 and GSK3β genes.

Presenilin‐2 knock‐In mice show severe depressive behavior via DVL3 downregulation

“…50 In addition, DVL3 is involved in the pathogenesis of MDD in female Chinese Han patients. 32 In agreement with these data, we also found that the cortisol levels of PS2 knock-in mice were higher than those of PS2 WT mice. These results…”

“…It was also demonstrated that the mRNA and protein levels of DVL3 in healthy individuals are significantly different from those of depressed individuals 50 . In addition, DVL3 is involved in the pathogenesis of MDD in female Chinese Han patients 32 . In agreement with these data, we also found that the cortisol levels of PS2 knock‐in mice were higher than those of PS2 WT mice.…”

“… 31 Other research has indicated that APP‐PS1 AD mouse brains have lower levels of DVL3 and increased levels of activated GSK3β than WT mouse brains. 32 Moreover, treatment with lithium, a GSK3β inhibitor, showed recovery levels of DVL3 accompanied by inhibition of GSK3β activity in APP‐PS1 AD‐related mouse brains. 33 Other research indicates that DVL‐GSK3β signaling was activated in depression‐like behaviors.…”

“…Overexpression of mouse DVL1 or DVL2 has been shown to inhibit GSK3β‐mediated phosphorylation of tau 31 . Other research has indicated that APP‐PS1 AD mouse brains have lower levels of DVL3 and increased levels of activated GSK3β than WT mouse brains 32 . Moreover, treatment with lithium, a GSK3β inhibitor, showed recovery levels of DVL3 accompanied by inhibition of GSK3β activity in APP‐PS1 AD‐related mouse brains 33 .…”

The Role of Sex in Genetic Association Studies of Depression

“…Variants in the CRHR1 gene have also been shown to have a protective effect on developing depression after childhood trauma among males, but not females [ 54 ]. There was a significant association between disheveled 3 ( DVL3 ) and glycogen synthase kinase 3 beta ( GSK3β ) variants, both involved in the Wnt pathway that is implicated in oxidative stress, and the risk of developing MDD among Chinese Han women [ 55 ]. An additional study found a significant sex-by-SNP interaction on depression for APOE in patients with Alzheimer’s disease such that women with the APOE epsilon4 allele were almost 4 times more likely to have depression than those without the APOE epsilon4 genotype [ 56 ].…”