The serotonin 2C (HTR2C) receptor has been implicated in suicide-related behaviours, however there are not many studies to date about HTR2C and suicidality. We studied HTR2C haplotypes in suicide attempters, where our sample composed of 306 families with at least one member affected by bipolar disorder. HTR2C (Cys23Ser and a common STR in the promoter) variants were analyzed with respect to attempter status and the severity of suicidal behaviour. The X-linked haplotype analysis in relation to suicide attempt did not reveal any significant association. Furthermore, we performed a particular gene-gene interaction for the X-linked serotonergic genes (HTR2C and MAOA), and found no association among this intergenic haplotype combination and suicidal behaviour in bipolar disorder.
This study aimed to determine the distributions of the age at onset (AAO) in patients with major depressive disorder (MDD) using admixture analysis and to determine the clinical differences between subgroups with different AAO.
Participants were administered the Mini-International Neuropsychiatric Interview to obtain clinical data. Admixture analysis was performed using the STATA module DENORMIX to identify subgroups characterized by differences in AAO.
The best fit model was the three-component model with the following means, standard deviations and proportions: 14.60 (3.75) years (49.1%), 29.15 (6.75) years (34.1%) and 46.96 (6.06) years (16.8%) (?(2)=3.64, 2 df, P=.162). The three subgroups were divided by AAO of 22 and 40. After controlling for duration of illness, there were no significant differences between the three AAO subgroups in terms of gender and psychiatric family history. However, the early-onset subgroup was significantly more likely to report being single compared to the intermediate- and late-onset groups. The proportion of individuals meeting criteria for lifetime comorbid panic disorders and obsessive-compulsive disorder did not differ significantly between the AAO groups. However, the early-onset group reported a higher incidence of attention-deficit/hyperactivity disorder (5.1% vs. 1.7% and 1.2%, P=.086), although this was not statistically significant.
Our study identified three characteristically different AAO subgroups in individuals suffering from MDD. The subgroups may reflect different underlying neurobiological mechanisms involved.
Cites: J Am Acad Child Adolesc Psychiatry. 1994 Nov-Dec;33(9):1289-987995795
The objective was to assess the presence of different subgroups, via age-at-onset (AAO) analysis, in a schizophrenia population consecutively recruited through an Early Psychosis Service in London, Canada.
Admixture analysis was applied in order to identify a model of separate normal distribution of AAO characterized by different means, variances and population proportions to allow for evaluation of different subgroups in a sample of 187 unrelated patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia.
The best-fitting model suggested three subgroups with means and standard deviations of 16.8 ± 1.9, 22.3 ± 2.1 and 32.7 ± 5.9 years comprising 41%, 30% and 29% of the schizophrenia sample, respectively. These three subgroups were categorized as early, intermediate and late onset with cutoffs determined by admixture analysis to be 19 and 26 years of age, respectively. In our investigation, the definition of early-onset schizophrenia is the main outcome. We considered the clinical variables mainly related to the heritability and neurobiology of schizophrenia. Single status was strongly associated with early onset (P
This study aimed to determine the distributions of the age at onset (AAO) using mixture analysis and better develop the understanding of AAO as a clinical feature of obsessive-compulsive disorder.
Mixture analysis was used to identify sub-groups characterized by differences in AAO. Clinical features were analyzed for differences in AAO sub-groups using mixture analysis. Comparisons were made with AAO cut-offs used in previous studies using the 2-Sample Kolmogorov-Smirnov Test.
Mixture analysis of our sample (n=196) yielded a combination of 2 normal theoretical distributions with means (SD) of 9.66 (3.12) for the early-onset sub-group and 21.1 (8.36) years for the late-onset sub-group. The sub-groups were divided by a cut-off of 15 years. As expected, a negative correlation was found between AAO and duration of illness. The early-onset subjects had significantly lower age at the time of the assessment and they tended to have more often panic attacks but were treated less often with benzodiazepines and other anti-anxiety medications. The comparison analysis showed significant difference in the AAO distribution between our sample and four other study samples.
Our findings support the notion that different AAO sub-groups correspond with differences in clinical presentations of obsessive-compulsive disorder.
Excessive or deficient levels of extracellular dopamine have been hypothesized to contribute to a broad spectrum of mood, motor, and thought abnormalities, and dopaminergic system genes have been implicated in aggressive behaviour from animal and human studies. OBJECTIVE. We examined selected members of the dopaminergic system genes for association with child aggression.
We analyzed polymorphisms in the dopamine transporter DAT1/SLC6A3, dopamine receptor DRD2, and DRD4 genes in our sample of pervasive childhood aggression consisting of 144 cases paired with 144 healthy controls, matched for sex and ethnicity.
Aggressive children were significantly more likely to have the at least one copy of the G allele for the DRD2 A-241G polymorphism (genotypic P=0.02; allelic P=0.01). The DRD2 rs1079598 CC genotype was overrepresented in aggressive children compared to controls (genotype P=0.04). The DRD2 TaqIA T allele (P=0.01) and the TT genotype (P=0.01) were also significantly overrepresented in aggressive children.
Our preliminary results suggest that three polymorphisms in DRD2 are associated with childhood aggression. Future studies are required to replicate the current results and to further explore the relationship between the dopamine system and aggressive behaviour in children.
Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).
Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.
Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.
The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.
Cites: PLoS Genet. 2006 Dec;2(12):e19017194218
Cites: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7501-619416921
Based on the dopaminergic hypothesis, the dopamine D(1) receptor gene (DRD1) is considered to be a good candidate gene involved in the susceptibility of bipolar disorder (BP). Genetic association between three DRD1 single nucleotide polymorphisms (SNPs) (-800T/C, -48A/G, and 1403T/C) and bipolar type I (BP I) disorder was performed in a case-control sample of Sardinian origin (170 BP I and 209 controls) and in an enlarged sample (229 families) of BP I trios from Toronto. The haplotype analyses generated significant global chi-square in both samples (P-value 0.024 in Toronto and 0.00042 in Sardinian). The main representative haplotypes in both samples were the -800T/-48A/1403C and the -800C/-48G/1403T. Considering each group individually, the -800C/-48G/1403T was transmitted more frequently from parents to BP I probands in Toronto sample (nominally P-value = 0.047) and was more frequent in cases than in control subjects in Sardinian sample although showing no significant evidence of association (nominally P-value = 0.16) When the estimated haplotype counts of both samples were combined, the global chi(2) was significant (P-value = 0.00085) and the nominal P-value for the haplotype -800C/-48G/1403T was 0.01. The fact that the same haplotype shows a similar trend for association in samples originating from different ethnic backgrounds seems to imply that the -800C/-48G/1403T haplotype may be considered as a risk factor for BP I disorder.
The goal of this research was to describe the relationship between treatment resistant schizophrenia, defined using the APA criteria and ethnic background in patients with schizophrenia spectrum disorders in a Canadian sample. A secondary goal was to analyze the number of antipsychotics failed due to side effects and number of antipsychotics failed due to non-response.
We included 497 patients diagnosed with schizophrenia spectrum disorders using the SCID. The medication history was extracted from the electronic health records. Data collection included demographics (sex, age, ethnicity), principal diagnosis according to SCID (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), duration of mental illness, number of psychiatric admissions and treatment information. If patients were on clozapine or polypharmacy treatment, this was recorded at the time of the SCID interview. Additional data, including prior antipsychotic history, were collected from the health records.
Thirty per cent of the patients were classified as resistant according to the APA criteria. There were significantly more white European subjects in the treatment resistant group (p=0.031). The duration of illness was significantly higher in the resistant group then in the non-resistant group (21.0 vs 15.1 years; p