Association study of GABRG2 polymorphisms with suicidal behaviour in schizophrenia patients with alcohol use disorder

BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder where the role of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, has been implicated in its aetiopathophysiology. Several genes coding for GABAA subunits, including the GABRG2 gene that encodes the γ2 subunit, are clustered at 5q31-q35, a chromosomal region that is associated with schizophrenia in genome scan studies. We recently reported GABRG2 to be associated with schizophrenia in our case-control and family samples. METHODS: We tested eight single-nucleotide polymorphisms spanning the GABRG2 gene for an association with suicidal behaviour in our schizophrenia sample of European ancestry (n = 197), taking into account history of alcohol abuse or dependence. RESULTS: We found the haplotypes of the rs183294 and rs209356 markers to be significantly associated with history of suicide attempt (p < 0.01) as well as suicide specifier scores (p < 0.05). The association appeared to be originating in patients with a history of alcohol dependence or abuse. CONCLUSIONS: Taken together, the results of the present study suggest that GABRG2 may be involved in suicidal behaviour in schizophrenia patients with alcohol dependence or abuse, but replications are required. These results may help in the discovery of novel treatments for alcoholism and/or prevention of suicide

The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis

Suicide is a prominent public health problem. Its aetiology is complex, and the brain-derived neurotrophic factor (BDNF) has been implicated. We performed the first meta-analysis of the functional BDNF marker Val66Met (rs6265, 196G>A) in suicidal behaviour using data from 11 previously published samples plus our present sample (total n=3352 subjects, 1202 with history of suicidal behaviour. The meta-analysis including all 12 studies showed a trend for the Met-carrying genotypes and Met allele conferring risk for suicide (random-effects model p=0.096; ORMet-carrier=1.13, 95% CI 0.98-1.30, and random-effects model p=0.032; ORMet=1.16, 95% CI 1.01-1.32, respectively). Furthermore, we found the Met allele and the Met allele-carrying genotypes to be associated with history of suicide attempt (eight studies; allelic meta-analysis - random-effects model: p=0.013; fixed-effects model: p=0.006; genotypic meta-analysis - random-effects model: p=0.017; fixed-effects model: p=0.008). Taken together, the results from our study suggest that BDNF Val66Met is involved in suicidality. Further studies are required to elucidate its role in suicidal behaviour

Association study of BDNF and DRD3 genes in schizophrenia diagnosis using matched case-control and family based study designs

Schizophrenia (SCZ) is a severe neuropsychiatric disorder with prominent genetic etiologic factors. The dopamine receptor DRD3 gene is a strong candidate in genetic studies of SCZ because of the dopamine hypothesis of SCZ and the selective expression of D(3) in areas of the limbic system implicated in the disease. We examined 15 single-nucleotide polymorphisms (SNPs) in DRD3 in our sample of European origin consisting of 95 small nuclear SCZ families and 167 case-control pairs. We also examined four BDNF SNPs in our samples because of evidence for BDNF regulation of DRD3 expression (Guillin et al., 2001). We found a nominally significant genotypic association with rs7633291 and allelic association with rs1025398 alleles. However, these observations did not survive correction for multiple testing. We did not find a statistically significant association with the other DRD3 and BDNF polymorphisms. Taken together, the results from the present study suggest that BDNF and DRD3 may not be involved in SCZ susceptibility

Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders

Objectives. Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Dwivedi et al., Arch Gen Psychiatry 2010;60:804-815; Zai et al., Prog Neuropsychopharmacol Biol Psychiatry 2012;34:1412-1418) and BDNF regulates the expression of the dopamine D3 receptor. Objective. We examined the role of the BDNF and DRD3 genes in suicide. Methods. We analysed four tag single-nucleotide polymorphisms (SNPs) in BDNF and 15 SNPs in the D3 receptor gene DRD3 for possible association with suicide attempt history in our Canadian sample of Schizophrenia (SCZ) patients of European ancestry (N = 188). Results. In this sample, we found a possible interaction between the BDNF Val66Met and DRD3 Ser9Gly SNPs in increasing the risk of suicide attempt(s) in our SCZ sample. Specifically, a larger proportion of SCZ patients who were carrying at least one copy of the minor allele at each of the Val66Met and Ser9Gly functional markers have attempted suicides compared to patients with other genotypes (Bonferroni P < 0.05). However, we could not replicate this finding in samples from other psychiatric populations. Conclusions. Taken together, the results from the present study suggest that an interaction between BDNF and DRD3 may not play a major role in the risk for suicide attempt, though further studies, especially in SCZ, are required

Ependymal cell contribution to scar formation after spinal cord injury is minimal, local and dependent on direct ependymal injury

Ependyma have been proposed as adult neural stem cells that provide the majority of newly proliferated scar-forming astrocytes that protect tissue and function after spinal cord injury (SCI). This proposal was based on small, midline stab SCI. Here, we tested the generality of this proposal by using a genetic knock-in cell fate mapping strategy in different murine SCI models. After large crush injuries across the entire spinal cord, ependyma-derived progeny remained local, did not migrate and contributed few cells of any kind and less than 2%, if any, of the total newly proliferated and molecularly confirmed scar-forming astrocytes. Stab injuries that were near to but did not directly damage ependyma, contained no ependyma-derived cells. Our findings show that ependymal contribution of progeny after SCI is minimal, local and dependent on direct ependymal injury, indicating that ependyma are not a major source of endogenous neural stem cells or neuroprotective astrocytes after SCI