Mechanism:

  • Our luciferase reporter assay demonstrated that the minor A allele of rs3755557 supported twice the level of the expression levels compared to the major T allele (R).
  • This study has demonstrated that rs3755557, a SNP in the promoter region of GSK3B, modulates gene expression by altered binding of transcription factors and is significantly associated with intracranial volume across three cohorts of healthy adults (total n = 776) (R).
  • The minor "A" allele results in higher GSK3B transcription. As shown in Figure 1A, mean expression from the major "T" allele promoter constructs were significantly lower than those from the minor "A" allele (0.4 fold expression relative to the A allele) (R).
  • An increase of transcription factor binding affinities results in a higher promoter activity of the risk allele. (R)
  • Rs3755557 regulates kinase energy metabolism. (R)
  • Unregulated expression causes a series of serious problems such as dysfunctions of the AKT, WNT signaling pathway, the mesocorticolimbic DA system. (R)
  • Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037–0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082–0.144). (R)

The Minor “A” Allele is Associated With:

  • a 52.9 % greater risk for schizophrenia compared with the major allele (R)
  • increased genetic vulnerability to TD manifestation in schizophrenia subjects with European Caucasian background (more studies needed to confirm) (R)
  • increased risk for ADHD (study only done in Korean population) (R)
  • significantly increasing the risk for AD in individuals with at least one other GSK3B polymorphism (R)
  • associated with reduced intracranial volume and gray matter (R)

The Major “T” Allele is Associated With:

  • a higher lithium response in patients with bipolar illness (R)
  • a decreased risk of schizophrenia (R)

rs3755557

Parent Gene: GSK3B

Importance: 5
Less common allele: A = 15%
More common allele: T = 85%
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