GABRB2 in Neuropsychiatric Disorders: Genetic Associations and Functional Evidences

Abstract

Background: The inhibitory GABAergic system has shown an association with multiple psychiatric disorders. The type A GABA receptors are an integral component of this system, and in recent years, evidence has accumulated to support an essential role in disease etiology for one of the receptor genes GABRB2 which encodes for the receptor β2 subunit. Objective: To summarize the different lines of evidence supporting the important role of GABRB2 in psychiatric disorders, with a particular focus on schizophrenia, and evaluate the recently-proposed GABRB2-origin of schizophrenia hypothesis. Results: In terms of genetics, Single Nucleotide Polymorphisms (SNPs) in GABRB2 have been associated with a number of psychiatric disorders, and some of the associations have remained significant following meta-analysis. Importantly, expression and alternative splicing of the gene was shown to be dependent on the genotypes of the associated SNPs, and receptors containing the long isoform displayed functional differences compared to those containing the short isoform. Moreover, differential epigenetic regulation and imprinting imbalance of the gene were observed in schizophrenic patients compared to healthy subjects. Finally, recent findings from a Gabrb2-knockout mouse model demonstrated that knockout of the gene alone was sufficient to induce a wide range of schizophrenia- like symptoms and comorbid phenotypes. Conclusion: The different lines of evidence coalesce to strongly support the recentlyproposed GABRB2-origin of schizophrenia hypothesis, and GABRB2 may also have a potential role in cognition, the dysfunction of which is common to many psychiatric disorders.

The light response in chickens divergently selected for feather pecking behavior reveals mechanistic insights towards psychiatric disorders

“…GABRB2 is an ionotropic type A γ-aminobutyric acid (GABA) receptor, which has been linked to schizophrenia in multiple studies (reviewed in [ 12 ]). Downregulation of multiple miRNAs has been shown to have an impact on GABRB2 protein levels in humans with internet gaming disorder [ 13 ].…”

Highly Recurrent Copy Number Variations in GABRB2 Associated With Schizophrenia and Premenstrual Dysphoric Disorder

“…These SCZ-associated SNPs, located in the vicinity of the AluYi6AH-151 insertion on GABRB2 ( 6 , 7 ), influenced genotype-dependent expression, and alternative splicing of the GABRB2 transcript giving rise to a reduced long-to-short isoform ratio of the β 2 subunit in SCZ brains ( 8 , 9 ). The reduced ratio in turn rendered the β 2 subunit-containing GABA A receptors less susceptible to fatigue upon repeated stimulation, thereby retarding the turn-off of inhibitory activity of the neurons in the face of lowered energy status ( 9 – 12 ). As a result, some of the haplotypes in the region such as H26 and H73 have been identified as protective, while other haplotypes such as H19 and H81 have been identified as susceptibility-enhancing, toward the development of SCZ ( 7 ).…”