Clement C. Zai

The role of oxytocin and oxytocin receptor gene variants in childhood-onset aggression

Aggressive antisocial behaviours are the most common reasons why adolescents are referred to mental health clinics. Antisocial behaviours are costly in social and financial terms. The aetiology of aggressive behaviours is unknown but growing evidence suggests it is heritable, and certain genetic variants have been implicated as contributing factors. The purpose of this study was to determine whether genes regulating the hormone oxytocin (OXT) were associated with aggressive antisocial behaviour. The case‐control study sample consisted of 160 cases of children displaying extreme, persistent and pervasive aggressive behaviour. This case sample was compared with 160 adult controls. We used polymerase chain reaction (PCR) to determine the genotype for three oxytocin gene (OXT) single nucleotide polymorphisms (SNPs): rs3761248, rs4813625 and rs877172; and five oxytocin receptor gene (OXTR) SNPs: rs6770632, rs11476, rs1042778, rs237902 and rs53576. Genotypic analyses were performed using stata, while differences in haplotypic and allelic frequencies were analysed using Unphased. We also performed within‐case analyses (n = 236 aggressive cases) examining genotypic and allelic associations with callous‐unemotional (CU) scores (as measured by the psychopathic screening device). OXTR SNPs rs6770632 and rs1042778 may be associated with extreme, persistent and pervasive aggressive behaviours in females and males, respectively. These and haplotype results suggest gender‐specific effects of SNPs. No significant differences were detected with respect to CU behaviours. These results may help to elucidate the biochemical pathways associated with aggressive behaviours, which may aid in the development of novel medications.

Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis

AIMS This study aims to test for possible associations between the gene coding for the 5-HT2C receptor and antipsychotic-induced weight gain. MATERIALS & METHODS Four HTR2C polymorphisms (rs498207, C-759T, G-697C and Ser23Cys) were investigated in our sample of 205 chronic schizophrenia patients. RESULTS Significant over-representation of the C-G-Cys23 haplotype in patients with weight gain (OR: 1.93; 95% CI: 1.04-3.56; p = 0.0015) was found. Similarly, haplotype analyses of percentage weight change were also significant (p = 0.029) for the C-G-Cys23 haplotype associated with the highest average percent weight gain. Observations in the polymorphisms are consistent with previous studies. An updated meta-analysis of nine previous studies plus our current sample suggest that the -759C allele is associated with antipsychotic-induced weight gain. CONCLUSION Additional studies, including the resequencing of the region surrounding the HTR2C promoter, and functional studies of the promoter polymorphisms, may elucidate the mechanism underlying this genetic association.

A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in schizophrenia.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. ‘T’ allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21±4.51 vs 4.33±3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix–loop–helix/Per–Arnt–Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.

Maternal Immune Activation during Gestation Interacts with Disc1 Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice

Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors. DISC1 is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouse Disc1 gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) and Disc1-Q31L+/− offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age. Disc1-L100P+/− mutants were more sensitive to MIA than WT or Disc1-Q31L+/− mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain in Disc1-L100P+/− mice compared with WT or Disc1-Q31L+/− mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes in Disc1-L100P+/− mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P+/−) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction.

Childhood aggression, callous-unemotional traits and oxytocin genes

Given the known behavior effects of oxytocin, and in particular its putative effect on trust, affiliation and anxiety, we hypothesized that oxytocin may be involved in the development and expression of callous-unemotional traits in children with aggressive antisocial behavior. We recruited 162 children between the ages of 6 and 16. The majority of subjects were Caucasian (84.0%) compared to African-Canadian (4.9%) and others (11.1%). The oxytocin and oxytocin receptor gene polymorphisms were genotyped and analyzed for possible association with child aggression in a case–control study design as well as with callous-unemotional traits in a within cases analysis. We did not have significant findings with our tested OXTR markers in the case–control analysis. We found the OXTR_rs237885 AA genotype carriers to score higher than AC or CC genotype carriers on the callous-unemotional traits. This result remained significant following correction for multiple testing. No other markers were found to be significant. However, the haplotype consisting of the OXTR_rs237885 A allele and OXTR_rs2268493 A allele was associated with significantly higher callous-unemotional scores than other haplotypes. This is the first known study to show a significant association between callous-unemotional traits in children and adolescents with extreme, persistent pervasive aggression and a polymorphism on the oxytocin receptor. Given the small sample size and the possibility of false positive effects, the need to replicate and verify these findings is required.

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.

Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients.

Meta-analysis of two dopamine D 2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients

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.

Linkage study of two polymorphisms at the dopamine D3 receptor gene and attention‐deficit hyperactivity disorder

Data from animal studies suggest that the dopamine D3 receptor gene may have a role in locomotion and behavioral regulation. Therefore, this gene has been suggested as a candidate for attention-deficit hyperactivity disorder (ADHD). The dopamine D3 receptor gene (DRD3) has two common polymorphisms, one in exon I that changes a Serine to Glycine (Ser9Gly) and alters the recognition site for the restriction enzyme MscI [Lannfelt et al., 1992]. The other common polymorphism is located in intron 5 and results in the change of a restriction site for MspI [Griffon et al., 1996]. We investigated the possibility of linkage of the dopamine D3 receptor gene in 100 small, nuclear families consisting of a proband with ADHD, their parents, and affected siblings. We examined the transmission of the alleles of each of these polymorphisms and the haplotypes of both polymorphisms using the transmission disequilibrium test [Spielman et al., 1993]. We did not observe biased transmission of the alleles at either polymorphism or any haplotype. Our findings using this particular sample do not support the role of the dopamine D3 gene in ADHD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:114-117, 2000.

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.