Family-based association study of the BDNF,COMT and serotonin transporter genes and DSM-IV bipolar-I disorder in children

Background

Over the past decade pediatric bipolar disorder has gained recognition as a potentially more severe and heritable form of the disorder. In this report we test for association with genes coding brain-derived neurotrophic factor (BDNF), the serotonin transporter (SLC6A4), and catechol-O-methyltransferase (COMT).

Methods

Bipolar-I affected offspring triads (N = 173) were drawn from 522 individuals with 2 parents in 332 nuclear families recruited for genetic studies of pediatric psychopathology at the Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD at Massachusetts General Hospital.

Results

We failed to identify an association with the val66 allele in BDNF (OR = 1.23, p = 0.36), the COMT-l allele (OR = 1.27, p = 0.1), or the HTTLPR short allele (OR = 0.87, p = 0.38).

Conclusion

Our study suggests that the markers examined thus far in COMT and SLC6A4 are not associated with pediatric bipolar disorder and that if the val66met marker in BDNF is associated with pediatric bipolar disorder the magnitude of the association is much smaller than first reported.

     

Relationship between cannabis use, schizotypal traits, and cognitive function in healthy subjects

This research examined the relationship between cannabis use and schizotypal features. A sample of cannabis users (n = 20) was compared with a matched control group (n = 20). All participants were male students of the University of Hamburg. Subjects completed the Perceptual Aberration Scale and the Schizotypal Personality Questionnaire. A Negative Priming procedure and the Trail Making Test were carried out. A urine sample was obtained from each subject. Cannabis users exceeded controls in schizotypy scores and showed impaired neuropsychological parameters. Only within the cannabis group schizotypy scores correlated with neuropsychological parameters. Furthermore, cannabis users reported more often high-risk factors than controls. These findings indicate that among cannabis users there is an increased number of subjects with schizotypal features; schizotypal subjects seem to be more likely to use cannabis than the general population. Therefore, cannabis use may be a vulnerability indicator for schizophrenia.     

Genetic association of the interaction between the BDNF and GSK3B genes and major depressive disorder in a Chinese population

Alterations in brain-derived neurotrophic factor (BDNF)-signaling pathways may play an important role in the pathophysiology of major depressive disorder (MDD). Several lines of evidence have suggested that gene–gene interactions may confer susceptibility to MDD. The aim of this study was to analyze the single and combined effects of genes in the BDNF signal-transduction pathway on MDD in a Chinese population. We recruited 447 patients with MDD and 432 age- and gender-matched control subjects. Five SNPs in three BDNF signal-transduction pathway genes (BDNF, GSK3B and AKT1) were used in association analyses. An allelic association between the GSK3B SNP rs6782799 and MDD was found in our sample (allelic: χ² = 5.24, P = 0.022, corrected P = 0.107; genotypic: χ² = 5.55, P = 0.062) with an odds ratio (OR) of 1.25 (95% confidence interval (CI) 1.03–1.52). Further gene–gene interaction analyses showed a significant effect of a two-locus BDNF/GSK3B interaction with MDD (GSK3B rs6782799 and BDNF rs7124442) (corrected P = 0.011), and also for a three-locus interaction (GSK3B rs6782799, BDNF rs6265 and BDNF rs7124442) (corrected P = 0.019). Individuals carrying the combination of two risk alleles showed an OR value of 4.00 (95% CI 2.05–7.79), while those with the combination of three risk alleles gave the largest OR value of 4.46 (95% CI 2.15–9.24). Taken together, these findings support the assertion that the GSK3B gene is an important susceptibility factor for MDD in a Han Chinese population.     

Lack of association between the BDNF gene Val66Met polymorphism and Alzheimer disease in a Chinese Han population

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and the cortex. Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for AD. Recently, several reports investigated the association between a single nucleotide polymorphism (Val66Met, rs6265) of the BDNF gene and AD but yielded ambiguous results. To figure out the association of this single nucleotide polymorphism in the BDNF gene with sporadic AD in a Chinese Han population, we analyzed 513 patients with AD and 575 controls for the genetic association studies. Our results indicated that the distribution of the BDNF genotypes and alleles did not differ significantly. Similar results were observed when the AD and control groups were stratified by age/age at onset and sex. Our data also showed that in the Chinese Han population, the frequencies of the BDNF Met allele (46.5%) and Val allele (53.5%) were significantly different from ethnic groups from Italy, Japan and the USA. The present data revealed no significant effect of the genotypes on the age at onset for developing AD, and no significant association between the genotypes and the severity of the disease.     

A family-based study of the association between the G72/G30 genes and schizophrenia in the Chinese population

Studies have shown a strong positive association between schizophrenia and G72/G30, demonstrated by both individual markers and haplotypes. A further functional study also supports the role of G72 in the etiology of schizophrenia. In this study, we have replicated these results of transmission/disequilibrium testing (TDT) and haplotype analysis in the Han Chinese population, showing P values of 0.0018 and 0.00007 for individual markers and haplotypes, respectively. Hence, our data supports the hypothesis that G72/G30 are important candidate genes for explaining schizophrenia in the Han Chinese population.     

An association study between 5-HTTLPR polymorphism, COMT polymorphism, and Tourette's syndrome

Several lines of evidence suggest that a genetic component underlies Tourette's syndrome (TS). We investigated both the role of the insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and that of the Val-158-Met substitution in the catechol-O-methyl-transferase (COMT) gene in conferring susceptibility to TS. Fifty-two TS patients were recruited and compared with a control group of 63 healthy subjects. Neither a genotypic nor an allelic association was found; subdividing TS patients according to clinical variables, such as a co-diagnosis of obsessive–compulsive disorder (OCD) and a positive family history for obsessive compulsive disorder or tics, also failed to reveal a significant association. The lack of significance for 5-HTTLPR and COMT polymorphisms in conferring liability to TS does not exclude a role of different functional polymorphisms in genes coding for serotonergic or dopaminergic structures in the etiology of TS. In fact, TS is a complex disorder and these genes most likely have only a minor genetic effect in its etiology.     

Effect of COMT Val158Met polymorphism on personality traits and educational attainment in a longitudinal population representative study

The COMT Val158Met polymorphism has been associated with anxiety and affective disorders, but its effect on anxiety-related personality traits varies between studies. Our purpose was to investigate the effect of COMT Val158Met on personality traits from adolescence to young adulthood in a population representative Caucasian birth cohort. Also its association with educational attainment and anxiety and mood disorders by the age 25 were examined. This analysis is based on the older cohort of the Estonian Children Personality Behavior and Health Study (original number of subjects 593). The personality traits were assessed when the participants were 15, 18 and 25 years old. COMT Val158Met had an effect on Neuroticism in females by age 25 (p = 0.001, Bonferroni-corrected for five traits), whereas female Val homozygotes scored the highest. In addition, the Conscientiousness scores of subjects with Val/Val genotype were decreasing in time, being the lowest by the age 25 (p = 0.006, Bonferroni-corrected for five traits). By the age 25, males with the Val/Met genotype had mainly secondary or vocational education, whereas female heterozygotes mostly had obtained or were obtaining university education. COMT Val158Met was not associated with anxiety or mood disorders in either gender. These results suggest that genes affecting dopamine system are involved in the development of personality traits and contribute to educational attainment.     

Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population

Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p < 0.01). The C-281A and val66met polymorphisms have been in a strong linkage disequilibrium (D′ = 0.9875; p < 0.05). The haplotype analysis has shown a tendency to a significantly lower frequency of the Met-C haplotype in the schizophrenia group compared to the controls.     

Effect of age and gender on schizotypal personality traits in the normal population

Aim:  There is some evidence that age and gender influence expression of schizotypal traits in the normal population. One important limitation of previous studies, however, is the restricted age range of subjects. The aim of the present study was therefore to investigate the effect of gender and age on schizotypal personality features.
Methods:  A total of 1024 participants aged between 16 and 90 were assessed using the schizotypal personality questionnaire. The effect of gender and age on schizotypal features was investigated. Confirmatory factor analysis was used to examine the factor structure of the scale in different age groups.
Results:  Male subjects scored higher than women in negative and disorganized-like symptoms. Female subjects scored significantly in social anxiety and odd belief subscales. Younger participants significantlyscored higher in reference, odd belief, unusual perceptual experiences, odd behavior and odd speech subscales. While decreases in schizotypy scores were gradual for most of the scales, increased disorganization in female subjects was restricted to late adolescence. Confirmatory factor analysis of the data supported modified versions of the Raine three-factor model across all age groups.
Conclusion:  Psychological changes related to adolescence and better social adaptation as a result of life experience might contribute to the age- and gender-related differences in schizotypy.     

Association between aggressiveness, schizotypal personality traits and cannabis use in Swiss psychology students

Associations between aggressiveness, schizotypal traits, and self-declared cannabis consumption were explored in Swiss psychology students (n = 205). Higher hostility levels were strongly associated with more pronounced schizotypal traits, whereas frequency of cannabis use was not. Therefore, earlier reported correlations might be due to a subgroup of hostile consumers.     

No association between the TPH A218C polymorphism and personality traits in Japanese healthy subjects

It has been suggested that the central serotonergic activity is implicated in personality traits. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. In the present study, the association between the TPH A218C polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) was examined in 345 Japanese healthy subjects. The TPH A218C polymorphism was determined by a PCR-RFLP method. There were no significant differences in the seven dimension scores of TCI among the A/A, A/C, and C/C genotype groups by the one-way ANOVA. There was a significant negative correlation between age and the NS scores. Females showed significantly higher scores of HA, RD, and ST, and significantly lower scores of SD than males. The multiple regression analysis using age, gender, and the TPH genotype as independent variables also showed no significant association between any dimension score and the genotype. The present study thus suggests that the TPH A218C polymorphism does not affect personality traits in Japanese healthy subjects.     

BDNF serum levels,but not BDNF Val66Met genotype,are correlated with personality traits in healthy subjects

Consisting evidence in animal models has suggested that alterations in brain-derived neurotrophic factor (BDNF) brain expression and release are involved in the pathogenesis of mental illnesses, such as, mood, anxiety, and eating disorders. This hypothesis is supported by data emerging from biochemical studies on serum BDNF levels and genetic studies on the functional polymorphism Val66Met in the BDNF gene in patients and control subjects. Anxiety-related personality traits are associated with several mental disorders. However, they are also measurable in non-affected subjects and, so, may represent a useful “endophenotype” to study the biological correlation of the vulnerability factors in the general population. In this study, we analyzed putative correlations in subjects unaffected by mental disorders between personality traits, serum BDNF levels (N = 107), and the BDNF Val66Met genotype (N = 217). Furthermore, we tested the possible interactions between these variables. A significant correlation has been observed between high scores of harm avoidance (HA) measured by the temperament and character inventory (TCI), and low BDNF serum concentration (r = −0.253, P = 0.009). In addition, an association has been evidenced between low BDNF levels in serum and the BDNF Val/Val genotype (P = 0.021). By analyzing putative concomitant effects of different variables on HA scores in a regression model, we observed a significant correlation only with BDNF serum concentrations (P = 0.022). The study results suggest that a decrease in serum BDNF concentrations may represent a biochemical marker associated with anxiety personality traits also retrievable in the general population.     

A case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population

The glutamatergic dysfunction hypothesis of schizophrenia implicates the genes involved in glutamatergic transmission as strong candidates for schizophrenia-susceptibility. Recent linkage and association studies have identified the glutamate receptor, ionotropic, delta 1 gene GRID1 on 10q22 as a strong candidate for schizophrenia. In this current association study, we genotyped five genetic variants within the GRID1 gene in 567 Chinese Han subjects recruited from Northeast of China (260 schizophrenics and 307 normal controls). Four SNPs, rs1902666 (P=0.024), rs2814351 (P=0.027), rs11591408 (P=0.0000107) and rs999383 (P=0.000093) were found to be significantly associated with schizophrenia. Haplotype analysis also revealed significance with global P values of 0.0081 and 0.00076 for SNPs 1-2 and SNPs 3-4-5 haplotypes, respectively. Our results strongly support previously reported association studies, implicating GRID1 in the etiology of schizophrenia.     

No association between polymorphism in tyrosine hydroxylase and personality traits in healthy Japanese subjects

The aim of the present study was to investigate whether there is an association between the (TCAT)_n repeat polymorphism in the tyrosine hydroxylase (TH) gene and personality. The (TCAT)_n repeat polymorphism in the TH gene was genotyped in 898 healthy Japanese subjects. Personality traits were evaluated using the Temperament and Character Inventory (TCI). There was no significant difference in the TCI scores of subjects with and without the T9 allele. Furthermore, no significant association was found between each genotype and the TCI scores, even when the TCI scores were compared with the homozygous genotype. These findings suggest that the (TCAT)_n repeat polymorphism in the TH gene does not contribute to the personality traits evaluated on the TCI in healthy Japanese subjects.