Identification of Interaction Between Serotonin Transporter and Glycogen Synthase Kinase-3β Gene Polymorphisms: Role in Susceptibility to Bipolar Disorder

Abstract

Background: Genetic correlates of diseases of complex inheritance may include variations in several genes lying within a network of linked biological processes. Synaptic mechanisms, such as serotonin neurotransmission and second (third) messengers (e.g., glycogen synthase kinase [GSK]), have been implicated in susceptibility to mood disorders, the actions of therapeutic drugs and manipulation of circadian rhythms. A better understanding of such gene networks may be useful to understand the biology and treatment of mood disorders. Methods: We studied the association between serotonergic and GSK-mediated signaling networks with bipolar affective disorder (BPAD). We analyzed two single nucleotide polymorphisms (SNPs) in the HTR2A gene, a promoter SNP in SLC6A4 and a promoter SNP in the GSK3B gene in BPAD individuals and matched controls. A multifactor dimensionality reduction tool was employed to study gene–gene interactions and analyze multilocus genotype combination associations with high- or low-risk of BPAD. Results: Multifactor dimensionality reduction detected the best interacting model involving 5-HTTLPR (SLC6A4) and rs334558 (GSK3B). Conclusion: Our results suggest interplay between the serotonergic pathway and the second-messenger system involving GSK, which are important drug targets.

Keywords:

• 5-HTTLPR
• bipolar disorder
• gene networks
• GSK3B
• multifactor dimensionality reduction

Financial & competing interests disclosure

Financial support from Department of Biotechnology, National Institute of Mental Health & Advanced Neurosciences, is duly acknowledged. D Subhashree is grateful to CSIR and ICMR for junior and senior research fellowships. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Acknowledgement

We thank the patients and healthy volunteers for their participation.

Additional information

Funding

Financial support from Department of Biotechnology, National Institute of Mental Health & Advanced Neurosciences, is duly acknowledged. D Subhashree is grateful to CSIR and ICMR for junior and senior research fellowships. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.