Agnieszka Slopien

Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder

Summary Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. A functional polymorphism Val66Met of BDNF gene was studied in patients with schizophrenia (n=336), bipolar affective disorder (n=352) and healthy controls (n=375). Consensus diagnosis by at least two psychiatrists, according to DSM-IV and ICD-10 criteria, was made for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID). No association was found between the studied polymorphism and schizophrenia or bipolar affective disorder either for genotype or allele distribution (for genotype: p=0.210 in schizophrenia, p=0.400 in bipolar disorder; for alleles: p=0.260 in schizophrenia, p=0.406 in bipolar disorder). Results were also not significant when analysed by gender. For males genotype distribution and allele frequency were (respectively): p=0.480 and p=0.312 in schizophrenia, p=0.819 and p=0.673 in bipolar affective disorder. Genotype distribution and allele frequency observed in the female group were: p=0.258 for genotypes, p=0.482 for alleles in schizophrenia; p=0.432 for genotypes, p=0.464 for alleles in bipolar affective disorder. A subgroup of schizophrenic (n=62) and bipolar affective patients (n=28) with early age at onset (18 years or younger) was analysed (p=0.328 for genotypes, p=0.253 for alleles in schizophrenia; p=0.032 for genotypes, p=0.858 for alleles in bipolar affective disorder).

Association Analysis of the GSK-3β T–50C Gene Polymorphism with Schizophrenia and Bipolar Disorder

Glycogen synthase kinase-3β (GSK-3β) has been implicated in the pathogenesis of major psychoses. In this paper, the T–50C polymorphism of the GSK-3β gene has been studied in patients with schizophrenia (n = 432), patients with bipolar disorder (n = 416) and in a healthy control group (n = 408). Consensus diagnosis by at least two psychiatrists was made for each patient, according to DSM-IV and ICD-10 criteria, using the Structured Clinical Interview for DSM-IV Axis I Disorders. Genotypes were established by the polymerase chain reaction-restriction fragment length polymorphism method. We have found a trend towards an association for the C allele in the whole group of schizophrenic patients (p = 0.088) and for the heterozygous T/C genotype of bipolar patients (0.095). Significant differences of genotype distribution and allele frequencies of the T–50C polymorphism were found in the female group of bipolar II patients (p = 0.015 for genotypes and p = 0.009 for alleles). In conclusion, this polymorphism may be associated with female gender in bipolar II disorder.

Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population.

Dysregulation of dopaminergic neurotransmission has been implicated in the etiology of major psychoses. The dopamine D1 receptor (DRD1) plays a role in some brain functions and mechanisms of psychotropic drugs. Therefore, the DRD1 gene makes a good candidate gene for molecular genetic studies in schizophrenia and bipolar affective disorder. In the present study, the –48A/G polymorphism of the DRD1 gene was estimated in patients with schizophrenia (n = 407) or bipolar affective disorder (n = 380), and in healthy controls (n = 399). No association was found between the polymorphism studied and schizophrenia, either in the whole group of patients or in subgroups divided by gender, age at onset or predominance of positive or negative symptoms. A statistical trend was obtained for an association between this polymorphism and bipolar affective disorder (p = 0.059 for genotypes, p = 0.073 for alleles). The G/G genotype and G allele were significantly more frequent in patients with bipolar disorder, type II (p = 0.016 for genotypes, p = 0.008 for alleles), especially in the women subgroup (p = 0.054 for genotypes, p = 0.024 for alleles). An association between the G/G genotype and bipolar affective disorder with disease onset after 18 years of age was also found (p = 0.022). These data suggest that the –48A/G polymorphism of the DRD1 gene may be involved in the etiology of bipolar disorder in a Polish population.

Association of Tumor Necrosis Factor –308G/A Promoter Polymorphism with Schizophrenia and Bipolar Affective Disorder in a Polish Population

Background/Aims: Schizophrenia (SCH) and bipolar affective disorder (BPAD) are complex disorders with significant participation of genetic risk factors. Several lines of evidence point to the role of shared neurobiological mechanisms and common genetic background in SCH and BPAD. Immune disturbances have been suggested as contributing factor in the pathogenesis of both SCH and BPAD. The gene coding cytokine tumor necrosis factor (TNF) has been the object of a number of association studies in SCH, with ambiguous results. Only 3 such studies were performed in BPAD. The aim of our study was to perform a case-control association analysis of the TNF –308G/A polymorphism in a Polish sample of patients with SCH, BPAD and healthy controls. Methods: We genotyped the TNF –308G/A polymorphism (rs1800629) by PCR-RFLP in 348 patients with SCH, 361 patients with BPAD and in 351 controls. Results: We observed an association of the –308G allele with both SCH (p = 0.008) and BPAD (p = 0.039), and also with a positive family history in patients with SCH (p = 0.048) and BPAD (p = 0.027). For TNF genotypes, the association was only seen in SCH (p = 0.018). Conclusions: Our results may point to an association of the TNF –308G allele and –308G/G genotype with both SCH and BPAD, and to a relationship of the –308G allele with the risk of SCH and BPAD in patients with a positive family history. TNF could be potentially a susceptibility gene, shared between SCH and BPAD. Complex TNF gene studies – based on multiple single-nucleotide polymorphisms and involving haplotype analysis – are necessary for the clarification of currently contradictory findings.

The 5-HT2A -1438 A/G and 5-HTTLPR polymorphisms and personality dimensions in adolescent anorexia nervosa: association study.

Disturbances of serotonergic neurotransmission and temperamental vulnerability have both been implicated in the pathogenesis of anorexia nervosa (AN). We genotyped the –1438 A/G polymorphism in the 5-HT2A receptor gene and serotonin transporter linked-polymorphic region (5-HTTLPR) in 132 adolescent subjects with AN and in 93 healthy controls. Personality dimensions in AN patients were assessed with the Temperament and Character Inventory. In a case-control model, we tested the hypothesis that these genetic variants confer susceptibility to AN. We also analyzed whether two polymorphisms show association with temperamental and character traits. No significant difference was found in the 5-HTTLPR frequency between AN patients and controls; however, there was a statistical trend towards a higher frequency of the A allele of the –1438 A/G polymorphism in patients than in controls (64.9 vs. 56.7%, χ2 test, p = 0.08). We also found a significant association between the A allele of this polymorphism and two temperamental traits. Patients homozygous for the A allele showed lower reward dependence than G/G homozygotes, and A/A homozygotes showed lower harm avoidance than heterozygotes. Low reward dependence and harm avoidance were more characteristic of the restrictive-type AN than of other subtypes of the disorder. No association of 5-HTTLPR with personality dimensions in AN patients was observed. Our results may suggest that the A allele of the –1438 A/G polymorphism confers some genetic risk for adolescent AN patients, especially in those with personality traits, which are typical of the restrictive-type AN.

No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia

Brain-derived neurotrophic factor (BDNF) regulates a variety of neuromodulatory processes during development, as well as in adulthood. It has been proposed as a risk factor for schizophrenia. We have investigated a possible association between schizophrenia and the C-270T polymorphism in the brain-derived neurotrophic factor (BDNF) gene in 397 schizophrenic patients and 380 control subjects. The diagnosis of schizophrenia was made for each patient by at least two psychiatrists, using DSM-IV and ICD-10 criteria in structured clinical interviews for DSM-IV Axis I disorders (SCID). No association was found between schizophrenia and the analyzed polymorphism, for either genotype or allele distribution (for genotype: p=0.513, for alleles: p=0.812). Differences were not statistically significant when analyzed separately by sex. For males, the differences for genotype distribution and allele frequency were p=0.078 and p=0.162 respectively and for females: p=0.441 and p=0.315. Thus, our data indicate that variations in the BDNF gene are unlikely to be an important factor in susceptibility to schizophrenia.

Serum Neurotrophin Concentrations in Polish Adolescent Girls with Anorexia Nervosa

Objectives: Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays an important role in weight regulation and eating behaviors as well as in the activity-dependent neuroplasticity underlying learning and memory behaviors involving the hippocampus. In anorexia nervosa (AN) patients, abnormal serum BDNF concentrations, cognitive impairments and specific personality traits have been traditionally observed. This study explores the levels of four serum neurotrophins [BDNF, neurotrophin 3 (NTF3), neurotrophin 4 (NTF4) and glial cell line-derived neurotrophic factor (GDNF)] with respect to their use as potential biomarkers for AN. This study also investigates any associations that might exist between serum neurotrophin levels and neurocognitive impairment or personality traits. Methods: Serum neurotrophin concentrations were measured in 60 AN patients (AN group) and 45 healthy controls (HC group). We correlated the serum levels of the four neurotrophins BDNF, NTF3, NTF4 and GDNF and the clinical type of anorexia. We also analyzed the relationship between serum neurotrophin levels and the Beck Depression Inventory, body mass index, executive functions by the Wisconsin Card Sorting test (WCST) and personality dimensions by the Temperament and Character Inventory (TCI) test. Results: Serum NTF4 concentrations were significantly lower when comparing all AN patients (34.7 ± 72.5 pg/ml) or restriction type AN patients (29.1 ± 62.5 pg/ml) with the HC group (58.4 ± 135.8 pg/ml; p = 0.004 and p = 0.005, respectively). A significant correlation (p < 0.005) between BDNF serum levels and patient personality dimensions as measured by the TCI test was observed. Furthermore, significant correlations were observed between NTF4 and GDNF serum levels and executive function as measured by the WCST. Conclusions: These data suggest that NTF4 might serve as a biomarker for AN. Furthermore, BDNF and GDNF serum levels appear to be associated with personality traits and executive function.

Temperament and Character Inventory (TCI) in adolescents with anorexia nervosa

Background: Female patients with anorexia nervosa differ significantly from the control women in various dimensions of personality. Objective: To investigate the personality dimensions measured with the Temperament and Character Inventory (TCI) in adolescent patients with restrictive-type and bulimic/purging-type anorexia nervosa (ANR and ANB, respectively), and contrast them with the results of control females. Methods: Sixty-one patients with anorexia nervosa (36 ANR and 25 ANB) and 60 controls were tested with the TCI. A concomitant assessment of depression, body mass index and age was made to evaluate the possible correlation with personality dimensions. Results: Adolescent ANR patients scored higher in persistence, harm avoidance and cooperativeness, and lower in novelty seeking and self-transcendence than control women. ANB patients scored in the middle between ANR and control females, but differences did not reach the significance level with either group, except for the self-transcendence dimension where they scored significantly higher than those with ANR. Conclusions: The deviations in temperamental profile of adolescent ANR are similar to those reported in adult patients. The ANB adolescent patients with anorexia nervosa show less prominent deviations from the personality of control women. With regard to the character dimension of cooperativeness, adolescents with ANR scored higher than controls, in contrast to the observations in adult patients. This may reflect the effect of illness on the development of character.

Attention-Deficit/Hyperactivity Disorder is Related to Decreased Weight in the Preschool Period and to Increased Rate of Overweight in School-Age Boys

OBJECTIVE Previous studies have associated attention-deficit/hyperactivity disorder (ADHD) with growth deviations and obesity. However, available data regarding the growth of children with ADHD in their early childhood are insufficient. Therefore, we aimed to examine whether there are differences in body size between preschool boys with and without ADHD. METHODS The study used cross-sectional and retrospective longitudinal data concerning 112 boys with ADHD and a community-based sample of 308 boys without ADHD. The groups were homogeneous in terms of socioeconomic status, place of residence, term of birth, and birth weight. The average age of diagnosis was 8.3 years, and none of boys had been treated with stimulants before they were 7 years of age. Comparisons were made at the ages of 2, 4, and 6 years, for World Health Organization (WHO)-norm-standardized height, weight, body mass index (BMI), prevalence of underweight, overweight, and obesity. Separate analysis were made for the cross-sectional measurements of current body size. RESULTS Boys with ADHD at the age of 2 had significantly lower z scores for weight (t=-1.98, p=0.04) and BMI (t=-2.09, p=0.04), and at the age of 4 for weight (t=-2.05, p=0.04) than the boys from the control group. A significantly lower percentage of overweight/obesity was observed in boys with ADHD at the age of 2 in comparison with the control group. At the age of 6, boys with ADHD were underweight more often. Cross-sectional analysis of current body size showed that boys with ADHD had lower z scores for height (t=-3.08, p=0.002) and higher z scores (t=3.13, p=0.002) for BMI. Overweight was more frequent in this group. CONCLUSIONS Preschool boys with ADHD (age of 2-6 years) have a tendency toward lower body weight than their peers. But in subsequent phases of development, they are shorter and more frequently overweight than boys without ADHD, when place of residence, socioeconomic status, term of birth, birth weight, comorbid conditions, and treatment are controlled.

Salivary alpha-amylase, secretory IgA and free cortisol as neurobiological components of the stress response in the acute phase of anorexia nervosa

Abstract Objectives One novel hypothesis of the pathogenesis of anorexia nervosa (AN) is the possible role of mental stress in hyperactivity of the autonomic nervous system (ANS) and of the hypothalamic–pituitary–adrenal (HPA) axis. Two components of stress response – salivary alpha-amylase (sAA) and free cortisol – have been proposed. They can be determined in saliva, which closely reflects their concentrations in plasma. The purpose of this study was to measure salivary free cortisol, sAA and their correlation to secretory IgA (sIgA) of patients with AN in comparison to the average population. Methods A controlled clinical trial was designed for a matched group of 47 AN patients and 54 healthy individuals. After clinical examination, unstimulated salivary samples were taken during the acute stage of AN (BMI < 15 kg/m2) in the first week of hospitalisation. An enzyme-linked immunosorbent assay (ELISA) suitable for measuring sAA, sIgA and free cortisol were used. Results Anorexic patients exhibited disturbances in sAA secretion, and significantly increased cortisol and sIgA levels with a distinct correlation between these two parameters. Conclusions The behaviour of cortisol, sAA and sIgA levels can be assessed as an effect of stress reaction among AN patients with hyperactivity of the HPA axis and ANS dysregulation. The effect of stress response can be assessed reliably in saliva.