Influence of GSK3β Polymorphisms on Psychiatric and Neurological Disorders: Recent Insights

1 November 2012

I read with great interest the recent article by Bai et al. [1]. Interestingly, recent data suggests that rs334558 polymorphisms of the GSK-3β gene may influence a number of psychiatric and neurological disorders besides amnestic-type mild cognitive impairment.

For instance, the response to antidepressants varies greatly with rs334558 polymorphism of the GSK-3β gene. The best response to antidepressants in rs334558 C carriers is seen in those who expressed 5-HTTLPR s/s homozygosity [2]. On the other hand, those who display 5-HTTLPR l/ l homozygosity show the best response to antidepressant treatment in rs334558 T/ T carriers. These results have been confirmed by Tsai et al. in a recent study [3]. Similarly, the rs334558 polymorphisms influence the grey matter volume in temporal lobes in individuals with schizophrenia. For example, larger brain volumes in Brodmann area 21 are seen in those patients who carry the C allele [4].

Similarly, mutations at the rs334558 locus of the GSK-3β gene may result in altered brain function resulting in amnestic mild cognitive impairment. Impaired regional activation in the right superior frontal gyrus is seen more commonly in the T allele. Similarly, TT/CT carriers at the rs334558 locus have accentuated rSFG connectivity. Amnestic mild cognitive impairment in turn is a risk factor for developing Alzheimer’s disease. A direct increased risk of late onset Alzheimer’s disease is also seen in those who exhibit the T allele at rs334558 [5]. The -157T/-50T haplotype in particular increases the risk of developing late onset Alzheimer’s disease, especially in the Han Chinese population.

Similarly, the rs334558 polymorphism increases susceptibility to multiple sclerosis. For instance, individuals with the rs334558 GG genotype are almost 1.6 times more likely to develop multiple sclerosis [6]. The rs334558 GG particularly affects the rate of gene transcription and is especially associated with the relapsing remitting subtype of multiple sclerosis.

The above examples clearly illustrate the significant role that rs334558 polymorphisms of the GSK-3β gene play in psychiatric as well as neurological disorders and the need for further studies in this regard.

Shailendra Kapoor, M.D.
Mechanicsville, VA
Tel: 865-607-1014;


[1]        Bai F, Shi Y, Yuan Y, Yue C, Zhuang L, Xu X, Liu X, Zhang Z (2012) Association of a GSK-3β polymorphism with brain resting-state function in amnestic-type mild cognitive impairment. J Alzheimers Dis 32, 387-396.
[2]        Benedetti F, Dallaspezia S, Lorenzi C, Pirovano A, Radaelli D, Locatelli C, Poletti S, Colombo C, Smeraldi E (2012) Gene-gene interaction of glycogen synthase kinase 3-beta and serotonin transporter on human antidepressant response to sleep deprivation. J Affect Disord 136, 514-519.
[3]        Tsai SJ, Liou YJ, Hong CJ, Yu YW, Chen TJ (2008) Glycogen synthase kinase-3beta gene is associated with antidepressant treatment response in Chinese major depressive disorder. Pharmacogenomics J 8, 384-390.
[4]        Benedetti F, Poletti S, Radaelli D, Bernasconi A, Cavallaro R, Falini A, Lorenzi C, Pirovano A, Dallaspezia S, Locatelli C, Scotti G, Smeraldi E (2010) Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-beta activity. Genes Brain Behav 9, 365-371.
[5]        Zhang N, Yu JT, Yang Y, Yang J, Zhang W, Tan L (2011) Association analysis of GSK3B and MAPT polymorphisms with Alzheimer's disease in Han Chinese. Brain Res 1391, 147-153.
[6]        Galimberti D, Macmurray J, Scalabrini D, Fenoglio C, De Riz M, Comi C, Comings D, Cortini F, Villa C, Serpente M, Cantoni C, Ridolfi E, Fardipoor MH, Leone M, Monaco F, Bresolin N, Scarpini E (2011) GSK3beta genetic variability in patients with multiple sclerosis. Neurosci Lett 497, 46-48.