Gwyneth Zai

5HT1Dβ Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder: further evidence from a family-based association study

Obsessive-Compulsive Disorder (OCD) is a psychiatric condition with strong evidence for a genetic component and for the involvement of genes of the serotonin system. In a recent family-based association study we reported an association between the G allele of the G861C polymorphism of the 5HT1Dβ receptor gene and OCD. The aim of the present study was to further investigate for the presence of linkage disequilibrium between each of two polymorphisms of the 5HT1Dβ receptor gene and OCD in a larger sample of OCD families. In a total of 121 families the G861C and the T371G polymorphisms of the 5HT1Dβ receptor gene were genotyped using standard protocols. The genotyping data were analyzed with a new extension of the Transmission Disequilibrium Test (FBAT). The phenotypes considered in the analyses were the diagnosis of OCD and two quantitative phenotypes related to the diagnosis and clinically relevant, ie, the age at onset and the severity of OCD symptoms. We confirmed the previously found preferential transmission of the G861 allele to the affected subjects (z = 2.262, P = 0.02). No significant association was found between the polymorphism and the quantitative phenotypes considered. These results represent a confirmation of our previous published study and thus, could have important implications for the role of the 5HT1Dβ receptor gene in the pathogenesis and treatment of OCD. Further genetic investigations on this marker considering additional polymorphisms and other quantitative phenotypes related to OCD are warranted.

Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients

Tardive dyskinesia (TD) is a side-effect of chronic antipsychotic medication. Abnormalities in dopaminergic activity in the nigrostriatal system have been most often suggested to be involved because the agents which cause TD share in common potent antagonism of dopamine D2 receptors (DRD2), that notably is not balanced by effects such as more potent serotonin (5-HT)2A antagonism. Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD. The most consistent findings have been found with the Ser9Gly polymorphism of the DRD3 gene. Although DRD2 has long been hypothesized to be the main target for antipsychotics, only a few polymorphisms in DRD2 have been investigated for their potential involvement in the aetiology of TD. In the present study, we investigated 12 polymorphisms spanning the DRD2 gene and their association with TD in our European Caucasian (n=202) and African-American (n=30) samples. Genotype frequencies for a functional polymorphism, C957T (Duan et al., 2003; Hirvonen et al., 2004), and the adjacent C939T polymorphism were found to be significantly associated with TD (p=0.013 and p=0.022 respectively). DRD2 genotypes were not significantly associated with TD severity as measured by AIMS (Abnormal Involuntary Movement Scale) with the exception of a trend for C939T (p=0.071). Both TD and total AIMS scores were found to be significantly associated with two-marker haplotypes containing C939T and C957T (p=0.021 and p=0.0087 respectively). Preliminary results indicated that C957T was also associated with TD in our African-American sample (p=0.047). Taken together, the present study suggests that DRD2 may be involved in TD in the Caucasian population, although further studies are warranted.

Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor

A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder.1 The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to replicate this finding by testing for biased transmission of the alleles at this same polymorphism in a sample of 92 families with an ADHD proband. We did not observe significant evidence for biased transmission of the 148-bp allele, however we did observe biased transmission of two other alleles, the 136-bp allele and the 146-bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small, therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD.

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

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 (χ2 = 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 χ2 = 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.

Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder

Obsessive‐compulsive disorder (OCD) is a severe neuropsychiatric disorder with a strong genetic component, and may involve autoimmune processes. Support for this latter hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), with onset of OCD symptoms following streptococcal infections. Genes involved in immune response therefore represent possible candidate genes for OCD, including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune system. Four polymorphisms in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat (MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were investigated for the possibility of association with OCD using 160 nuclear families with an OCD proband. We examined the transmission of alleles of these four polymorphisms with the transmission disequilibrium test (TDT). A biased transmission of the 459‐bp allele (allele 2: χ2 = 5.255, P = 0.022) of MOG4 was detected, while MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype 1.13.2.2 (χ2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the family‐based association test (FBAT) was significant for MOG4 in total Yale‐Brown Obsessive‐Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further investigations combining genetic, pathological, and pharmacological strategies, are warranted.

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.

The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain.

BACKGROUND Brain-derived neurotrophic factor (BDNF) has extensive effects on the nervous system including cell survival, differentiation, neuronal growth and maintenance, as well as cell death. Moreover, it promotes synaptic plasticity and interacts with dopaminergic and serotonergic neurons, suggesting an important role on the alteration of brain function with antipsychotic medications and induced weight gain in schizophrenia patients. The differential effects of BDNF gene variants could lead to changes in brain circuitry that would in turn cause variable response to antipsychotic medication. Therefore, we hypothesized that genetic variation in this candidate gene helps in explaining the inter-individual variation observed in antipsychotic drug treatment with respect to response and induced weight gain. METHOD We examined four single-nucleotide polymorphisms across the BDNF gene, including Val66Met (rs6265). Prospective BPRS change scores and weight change after six weeks were obtained from a total of 257 schizophrenia patients of European ancestry. RESULTS The markers rs11030104 and Val66Met were associated with antipsychotic response (P=0.04; 0.007, respectively). On the other hand, marker rs1519480 was associated with weight gain (P=0.04). Moreover, a two-marker haplotype across rs6265 and rs1519480 was associated with weight change (P=0.001). Results with Val66Met in response, and results with rs6265-rs1519480 haplotypes remained significant at the modified Bonferroni corrected alpha of 0.017. CONCLUSION BDNF genetic variants might play an important role in predicting antipsychotic response and antipsychotic-induced weight gain. However, replication in larger and independent samples is required.

Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia.

A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed d-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the d-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes d-serine, a potent activator of the N-methyl-d-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.

Attention-deficit hyperactivity disorder and the adrenergic receptors α1C and α2C

The adrenergic system has been hypothesized to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD) based on pharmacological interventions and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study we tested the genes for two adrenergic receptors, α1C (ADRA1C) located on chromosome 8p11.2, and α2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor α1C we used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor α2C gene we examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. We examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. Using the transmission disequilibrium test, we did not observe biased transmission of any of the alleles of these polymorphisms. We conclude that the alleles at the polymorphisms tested in these two genes are not linked to the ADHD phenotype in this sample of families.

Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia

A serotonin transporter gene linked polymorphic region (5-HTTLPR) has been investigated in several genetic association studies, including studies of schizophrenia and suicidality. The current study was designed to examine whether the new long (A/G) variant polymorphism of the 5-HTT gene may be associated with suicide attempts of 290 Caucasian schizophrenic patients. Among these patients, 92 had a history of suicide attempt. No association with history of suicide attempt was found in the multiallelic 5-HTTLPR (p = 0.305), however we found significant association with the intron 2 VNTR polymorphism (p = 0.018). When we performed a haplotype analysis, we found association between suicide attempt and haplotype distribution (p = 0.031). These findings suggest that the intron 2 VNTR polymorphism in serotonin transporter gene may influence suicidal behaviour in schizophrenia.