Evidence for the gamma‐amino‐butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive‐compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) is a well-recognized severe neuropsychiatric illness. Genetic factors are believed to be important etiologically. Although historically genetic testing has focused on the serotonergic and dopaminergic systems, there is increasing evidence that the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), may also be functionally involved. Furthermore the GABA type B receptor 1 (GABBR1) gene has been localized to chromosome 6p21.3 region, which has shown linkage to OCD. We investigated five polymorphisms (A-7265G substitution; C10497G substitution; A33795G substitution in the 3'-UTR; Ser-491-Ser-T1473C transition; Phe-659-Phe-T1977C transition) in the GABBR1 gene in a sample of 159 DSM-IV OCD probands and their families, using the transmission disequilibrium test (TDT). A trend was observed with an over-transmission of -7265A allele at the A-7265G polymorphism and OCD (chi2 = 3.270, P = 0.071). Moreover, the TDT haplotype analysis using TRANSMIT showed a trend toward association with the haplotype of the five polymorphisms together [2.1.1.2.1 (A-7265G.C10497G.Ser-491-Ser.Phe-659-Phe.A33795G)] with a Chi-square value of 3.418, which corresponds to a P-value of 0.065 (overall chi2 = 6.353, 5 df, P = 0.273). Moreover, a trend was observed for the total Yale-Brown obsessive-compulsive scale score in the A-7265G polymorphism (-7265A: z = 1.934, P = 0.053) using the Family-Based Association Test, considering the diagnosis of OCD and then the clinically relevant quantitative phenotypes. The observed trends suggest that further investigations of the role of the GABBR1 gene in OCD are warranted.

Evidence for Cortical Inhibitory and Excitatory Dysfunction in Obsessive Compulsive Disorder

“…As described above, such deficits are consistent with proposed mechanisms of OCD pathogenesis (Rosenberg and Keshavan 1998). The observed deficits in GABA B receptor-mediated inhibition are consistent with a study implicating the GABA B receptor 1 (GABBR1) gene in susceptibility gene to OCD (Zai et al, 2005). Additionally, our findings of increased ICF in OCD are in line with a wellreplicated finding of association between the neuronal glutamate transporter gene SLC1A1 and OCD (Arnold et al, 2006;Dickel et al, 2006;Liang et al, 2008;Stewart et al, 2007).…”

“…Additional evidence supports the involvement of g-aminobutyric acid (GABA) and glutamatergic neurotransmission in OCD, including magnetic resonance spectroscopy studies, which suggest alterations in glutamate concentrations in the caudate in pediatric OCD (Rosenberg et al, 2000), and genetic studies implicating the glutamate transporter gene SLC1A1 (Arnold et al, 2006;Dickel et al, 2006), the glutamate N-Methyl-D-aspartate (NMDA) subunit receptor gene GRIN2B (Arnold et al, 2004;Dickel et al, 2006), as well as the GABA B receptor 1 (GABBR1) gene as susceptibility genes in OCD (Zai et al, 2005). Collectively the above represents compelling evidence that OCD is associated with deficient inhibition and excessive facilitation in the cortex.…”

Neural inhibition enables selection during language processing

“…Here we test the predictions of the model regarding selection processes that are supported by the left ventrolateral prefrontal cortex. We do so for the following reasons: (i) this region has been implicated in selecting among competing alternatives during language processing (6,(15)(16)(17)(18); (ii) this region shows altered activity in individuals who suffer from anxiety (particularly anxious apprehension, characterized by worry, and hereafter referred to as "anxiety" (19); and (iii) GABAergic function is reduced in individuals with anxiety (20)(21)(22)(23). Hence, our model provides a unified framework that can link these formerly disconnected observations.…”

Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions

“…In this case, the results suggest that OCD is associated with deficient cortical silent period and excessive intracortical facilitation, regardless of medication state, reflecting abnormalities in GABA B and NMDA-mediated neurotransmission, which is consistent with the reults of several genetic studies of this disorder. [76][77][78][79][80][81] The authors suggested that differences between their results and those previously published could be owing to the greater number of unmedicated patients and elevated symptom severity in their sample or to the different stimulation intensities used to elicit measures. The discrepant findings in the limited number of studies highlight the need for further research to better characterize the potential abnormalities seen in patients with OCD.…”