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No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia
Schizophrenia Research 76 (2005) 187 – 193 www.elsevier.com/locate/schres
No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia Aleksandra Szczepankiewicza,T, Maria Skibinskaa,b, Piotr M. Czerskia, Pawey Kapelskib, Anna Leszczynska-Rodziewiczb, Agnieszka Syopienc, Monika Dmitrzak-We˛glarza,c, Filip Rybakowskic, Janusz Rybakowskib, Joanna Hausera,b a
Laboratory of Psychiatric Genetics, University of Medical Sciences, ul. Szpitalna 27/33, 60-572 Poznan, Poland b Department of Adult Psychiatry c Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, Poznan, Poland Received 15 June 2004; received in revised form 10 February 2005; accepted 12 February 2005 Available online 23 March 2005
Abstract 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. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; BDNF; Polymorphism; Association analysis
1. Introduction
T Corresponding author. Fax: +48 61 8480 392. E-mail address: [email protected] (A. Szczepankiewicz). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.02.006
Genetically controlled abnormal molecular events during brain development could cause alterations in neurogenesis (i.e. changes in synaptic morphology and physiology and altered differentiation, migration
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and survival of neurons) and lead to later susceptibility for schizophrenia. Disturbance of these processes may involve neurotrophic factors (Arnold and Rioux, 2001). One of the candidate genes for these neurodevelopmental events is brain-derived neurotrophic factor (BDNF). Dysfunction of this protein has been postulated as a risk factor for psychiatric and neurological disorders (Thome et al., 1998; Siegel and Chauhan, 2000). Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors (Barde et al., 1982; Leibrock et al., 1989) and interacts with the tyrosine kinase receptor (trkB) (Squinto et al., 1991). BDNF has trophic effects on dopaminergic neurons (Altar et al., 1992; Shen et al., 1994; Shults et al., 1994), cholinergic neurons (Lindsay, 1995; Lindvall et al., 1994) and serotonergic neurons (White et al., 1994; Mamounas et al., 1995, 2000). It is also essential for the development of sensory ganglia, the cerebral cortex, hippocampus and striatum (Liu et al., 1995). BDNF affects neuronal proliferation, promotes midbrain dopaminergic neuron survival and synaptic plasticity and also influences hippocampal long term potentation (LTP), learning and memory (Lu and Gottschalk, 2000; Poo, 2001; Egan et al., 2003; Lu, 2003; Mizuno et al., 2003). The BDNF gene is localized in the short arm of chromosome 11 (11p13) (Maisonpierre et al., 1991). The gene consists of four short 5Vexons with separate promoters and one 3Vexon encoding mature BDNF protein (Timmusk et al., 1993; Metsis et al., 1993). Several polymorphisms of BDNF have been reported and studied in psychiatric disorders. The most frequent are the dinucleotide repeat polymorphism (GT)n in the promoter region, 1.4 kb from the transcription starting site (Proschel et al., 1992), the Val66Met (196G/A) polymorphism (Cargill et al., 1999), the 270C/T substitution (Kunugi et al., 2001), the 374A/T and the 256G/A polymorphisms (Ribases et al., 2003). The Val/Met polymorphism affects human memory and hippocampal function. According to Egan et al. (2003), Hariri et al. (2003), the Met allele is associated with abnormal hippocampal activation and impaired episodic memory in humans. Egan colleagues (2003a) reported a relationship between the BDNF Val/Met polymorphism and a reduced ability to perform in schizophrenia patients, suggesting an association of the Met
allele with impaired cognitive functions and a reduced ability to perform learning and memory tasks. In our previous study, we did not find an association between the Val/Met polymorphism and schizophrenia (Skibin´ska et al., 2004). Neves-Pereira et al. (2002), Sklar et al. (2002) reported an association of the Val variant of the Val66Met polymorphism and affective disorder. However others, including Nakata et al. (2003) did not confirm this finding. In our study (Rybakowski et al., 2003) we described an association between the Val/ Val genotype and earlier onset of bipolar disorder in comparison to patients with a heterozygous genotype. Moreover, we found a significant relationship between the performance in neuropsychological tests of prefrontal cortex function of bipolar patients and the Val/Met polymorphism. The Met allele is also associated with the restrictive type of anorexia nervosa (Ribases et al., 2003). This allele was found to have a protective effect in depression (Sen et al., 2003) and obsessive-compulsive disorder (Hall et al., 2003). An association of the dinucleotide repeat polymorphism (GT)n (blongQ alleles 172–176 bp) with the late age of onset and a better response to neuroleptic treatment in schizophrenic patients was reported by Krebs et al. (2000). In addition, an association of the A3 allele (170 bp) with schizophrenia was described by Muglia et al. (2003). However, this report was not consistent with previous results (Sasaki et al., 1997; Hawi et al., 1998; Wassink et al., 1999; Virgos et al., 2001). The 270C/T polymorphism was investigated in schizophrenia with both positive (Szekeres et al., 2003; Kunugi et al., 2001), and negative results (Galderisi et al., 2005). Negative results were also obtained in studies of anorexic and bulimic patients (Ribases et al., 2004). The two novel polymorphisms, 374A/T and 256G/A, were discovered by Ribases et al. (2003) in the screening analysis of the BDNF gene in patients with anorexia nervosa. However, no association analysis was performed. In this study, we investigated allelic distribution of the C-270T single nucleotide polymorphism (SNP) in the 5V noncoding region of the BDNF gene in a group of schizophrenic patients in comparison to a control group. We chose to investigate this polymorphism only because its
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localization and possible influence on changes in BDNF expression observed in schizophrenia.
2. Subjects and methods 2.1. Subjects The study was performed on 397 patients with schizophrenia (217 males with a mean age of 29.7 years, SD = 11.0 and 180 females with a mean age of 33.1 years, SD = 12.0). The patients were recruited from inpatients from the Wielkopolska region of western Poland treated in the Departments of Psychiatry of the Universities of Medical Sciences in Poznan and Bydgoszcz and the Psychiatric Hospital in Koscian. Consensus diagnosis according to DSM-IV and ICD-10 criteria was performed by at least two psychiatrists, for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID) (First et al., 1996). The control group consisted of 380 subjects (145 males with a mean age of 41.6 years, SD = 12.7 and 235 females with a mean age of 40.7 years, SD = 11.8). These controls were recruited from a group of blood donors, plus hospital staff and students from the Poznan University of Medical Sciences. They were not psychiatrically screened. The project was approved by the local ethics committee.
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6.2 Al at 37 8C with use of 0.7 units of HinfI restriction endonuclease (MBI Fermentas). Afterwards, the digestion products were separated on 3.5% basica LE agarose gel (Prona, Spain) with 90 V and visualised by ethidium bromide staining. Bands were compared to a pUC19DNA/MspI size marker and 50 bp DNA ladder (MBI Fermentas). The uncut PCR product was 223 bp. After RFLP analysis, the following alleles were observed: for the C allele, bands of 127 and 78 bp and for the T allele, bands of 127 and 63 bp. 2.3. Statistical analyses The Pearson’s chi-square (v 2) test and Fisher’s exact test were applied to test differences in the genotypic and allelic distribution, respectively, between the group of schizophrenic patients and the control subjects. Additionally, stepwise logistic regression analysis was performed for each diagnostic group, including the BDNF polymorphism and gender as covariates. All calculations were performed using the SPSS version 10 computer programme. A two-tailed type I error rate of 5% was chosen for analysis. Power analysis was performed using an on-line internet service provided by the UCLA Department of Statistics (http:// ebook.stat.ucla.edu/calculators/powercalc/binominal/ case-control/b-case-control-power.php).
2.2. Genotyping 3. Results DNA was extracted from 10 ml of EDTA anticoagulated whole blood, using the salting out method of Miller et al. (1988). A 223-basepair fragment of the BDNF gene was amplified by PCR reaction using the set of primers described by Kunugi et al. (2001) in a PTC-200 (MJ Research) thermal cycler. A 15 Al amplification mixture contained 150–300 ng of genomic DNA, 0.3 AM of each primer, 0.17 mM of each dNTP, 1.5 mM MgCl2, 75 mM Tris–HCl, 20 mM (NH4)2SO4, 0.01% Tween 20 and 0.4 U of Taq DNA polymerase (MBI Fermentas). The following PCR conditions were used: initial denaturation at 95 8C for 3 min. followed by 35 cycles with a profile of 94 8C for 30 s, 64 8C for 30 s, 72 8C for 30 s, and final elongation at 72 8C for 10 min. The PCR product (4.0 Al) was then digested overnight in a total volume of
The genotype distribution was in Hardy–Weinberg equilibrium for all the groups studied. The genotype and allele distributions for the patients with schizophrenia did not differ significantly from those in the control group ( p = 0.513 and p = 0.812, respectively) (Table 1). Also, when groups were divided according to gender, we did not find any significant differences in genotype and allele distribution (in the male group p = 0.151 for genotypes and p = 0.162 for alleles, respectively; in the female group p = 0.441 and p = 0.315, respectively). Only one female individual with a T/T genotype was present in the control group in our sample. However, it did not affect the genotype and allele frequency for the analyzed subgroup significantly.
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Table 1 Genotype distributions and allele frequencies of the BDNF C-270T polymorphism for patients with schizophrenia and the control group
Patients with schizophrenia Controls
Genotype C/C n (%)
Genotype C/T n (%)
Genotype T/T n (%)
Total genotypes n (%)
Allele C n (%)
Allele T n (%)
Total alleles n (%)
358 (90.2%)
39 (9.8%)
0 (0.0%)
397 (100%)
755 (95.1%)
39 (4.9%)
794 (100%)
346 (91.0%)
33 (8.7%)
1 (0.3%)
380 (100%)
725 (95.4%)
35 (4.6%)
760 (100%)
Patients with schizophrenia vs. controls—v 2 = 0.080, d.f. = 1, p = 0.513 for genotypes, p = 0.812 for alleles.
There was no association in logistic regression analysis between the analyzed BDNF polymorphism and schizophrenia (Wald test = 1.954, d.f. = 2, p = 0.617), after controlling for gender. The power to detect an association for relative risk, which in our sample was estimated as 1.75, was 77%.
4. Discussion In our study we did not find any association between the C-270T polymorphism in the BDNF gene and schizophrenia ( p = 0.513 for genotypes and p = 0.812 for alleles). We also did not find any sexspecific association. The functional significance of the C-270T substitution in the promoter region of BDNF is not clear. Changes in BDNF protein levels in the brain or serum of schizophrenic patients have been reported (Takahashi et al., 2000; Durany et al., 2001; Weickert et al., 2003), but there is no evidence that the C-270T polymorphism is responsible for such alterations in protein expression. Changes in BDNF expression were described in response to antipsychotic treatment (Angelucci et al., 2000; Linden et al., 2000; ChlanFourney et al., 2002) and to antidepressant therapy (Popoli et al., 2002; Coppell et al., 2003; Ivy et al., 2003). All these data make the BDNF gene a novel and promising target in association studies of schizophrenia, as well as in pharmacogenetic studies. Recent studies considering the C-270T polymorphism have included association analyses with schizophrenia, bipolar disorder, anorexia nervosa, bulimia nervosa and Alzheimer’s disease. Szekeres et al. (2003) found a strong association was found between heterozygous C/T genotype and T allele and a susceptibility to schizophrenia. Similar results were reported by Nanko et al. (2003) who found a weak, but significant excess of heterozygous C/T
genotype and the T allele and schizophrenia. However, Galderisi et al. (2005) found no differences in allele distribution between patients and controls. Analyses of association studies with other psychiatric disorders have shown different results. In their study of anorexia and bulimia, Ribases et al. (2004) detected an association between the C allele and weight loss and a high maxBMI in late age of onset with bulimia. In the same multinational study, allelic heterogeneity in distribution of the C-270T polymorphism was described. The T allele and heterozygous genotype were overrepresented only in a German sample, while in an Italian group allele C predominated. In a study of the C-270T polymorphism in Alzheimer’s disease in a German sample, a significant overrepresentation of the heterozygous C/T genotype was reported in these patients (Riemenschneider et al., 2002). The lack of association of the C-270T polymorphism with schizophrenia reported here is consistent with the recent study by Galderisi et al. (2005) who also did not detect an association of this polymorphism with schizophrenia. However, previous findings on this subject (Szekeres et al., 2003; Nanko et al., 2003) have reported an association between the T allele and the disease. This could be due to differences in the size of the samples analyzed (positive results: in Szekeres’s n = 101 and in Kunugi’s study n = 178; negative results in Galderisi’s n = 94 and n = 397 in our study). One should also consider the diversity of genotype and allele distribution between different populations which might be responsible for the differences in study results. Novel variants of BDNF gene were reported by Friedel et al. (2005) who screened the translated main exon of BDNF and identified three rare variants in German obese and underweight individuals: c.5C/T; c.273G/A; c.*137A/G. However, it is very unlikely
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No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia Aleksandra Szczepankiewicza,T, Maria Skibinskaa,b, Piotr M. Czerskia, Pawey Kapelskib, Anna Leszczynska-Rodziewiczb, Agnieszka Syopienc, Monika Dmitrzak-We˛glarza,c, Filip Rybakowskic, Janusz Rybakowskib, Joanna Hausera,b a
Laboratory of Psychiatric Genetics, University of Medical Sciences, ul. Szpitalna 27/33, 60-572 Poznan, Poland b Department of Adult Psychiatry c Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, Poznan, Poland Received 15 June 2004; received in revised form 10 February 2005; accepted 12 February 2005 Available online 23 March 2005
Abstract 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. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; BDNF; Polymorphism; Association analysis
1. Introduction
T Corresponding author. Fax: +48 61 8480 392. E-mail address: [email protected] (A. Szczepankiewicz). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.02.006
Genetically controlled abnormal molecular events during brain development could cause alterations in neurogenesis (i.e. changes in synaptic morphology and physiology and altered differentiation, migration
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and survival of neurons) and lead to later susceptibility for schizophrenia. Disturbance of these processes may involve neurotrophic factors (Arnold and Rioux, 2001). One of the candidate genes for these neurodevelopmental events is brain-derived neurotrophic factor (BDNF). Dysfunction of this protein has been postulated as a risk factor for psychiatric and neurological disorders (Thome et al., 1998; Siegel and Chauhan, 2000). Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors (Barde et al., 1982; Leibrock et al., 1989) and interacts with the tyrosine kinase receptor (trkB) (Squinto et al., 1991). BDNF has trophic effects on dopaminergic neurons (Altar et al., 1992; Shen et al., 1994; Shults et al., 1994), cholinergic neurons (Lindsay, 1995; Lindvall et al., 1994) and serotonergic neurons (White et al., 1994; Mamounas et al., 1995, 2000). It is also essential for the development of sensory ganglia, the cerebral cortex, hippocampus and striatum (Liu et al., 1995). BDNF affects neuronal proliferation, promotes midbrain dopaminergic neuron survival and synaptic plasticity and also influences hippocampal long term potentation (LTP), learning and memory (Lu and Gottschalk, 2000; Poo, 2001; Egan et al., 2003; Lu, 2003; Mizuno et al., 2003). The BDNF gene is localized in the short arm of chromosome 11 (11p13) (Maisonpierre et al., 1991). The gene consists of four short 5Vexons with separate promoters and one 3Vexon encoding mature BDNF protein (Timmusk et al., 1993; Metsis et al., 1993). Several polymorphisms of BDNF have been reported and studied in psychiatric disorders. The most frequent are the dinucleotide repeat polymorphism (GT)n in the promoter region, 1.4 kb from the transcription starting site (Proschel et al., 1992), the Val66Met (196G/A) polymorphism (Cargill et al., 1999), the 270C/T substitution (Kunugi et al., 2001), the 374A/T and the 256G/A polymorphisms (Ribases et al., 2003). The Val/Met polymorphism affects human memory and hippocampal function. According to Egan et al. (2003), Hariri et al. (2003), the Met allele is associated with abnormal hippocampal activation and impaired episodic memory in humans. Egan colleagues (2003a) reported a relationship between the BDNF Val/Met polymorphism and a reduced ability to perform in schizophrenia patients, suggesting an association of the Met
allele with impaired cognitive functions and a reduced ability to perform learning and memory tasks. In our previous study, we did not find an association between the Val/Met polymorphism and schizophrenia (Skibin´ska et al., 2004). Neves-Pereira et al. (2002), Sklar et al. (2002) reported an association of the Val variant of the Val66Met polymorphism and affective disorder. However others, including Nakata et al. (2003) did not confirm this finding. In our study (Rybakowski et al., 2003) we described an association between the Val/ Val genotype and earlier onset of bipolar disorder in comparison to patients with a heterozygous genotype. Moreover, we found a significant relationship between the performance in neuropsychological tests of prefrontal cortex function of bipolar patients and the Val/Met polymorphism. The Met allele is also associated with the restrictive type of anorexia nervosa (Ribases et al., 2003). This allele was found to have a protective effect in depression (Sen et al., 2003) and obsessive-compulsive disorder (Hall et al., 2003). An association of the dinucleotide repeat polymorphism (GT)n (blongQ alleles 172–176 bp) with the late age of onset and a better response to neuroleptic treatment in schizophrenic patients was reported by Krebs et al. (2000). In addition, an association of the A3 allele (170 bp) with schizophrenia was described by Muglia et al. (2003). However, this report was not consistent with previous results (Sasaki et al., 1997; Hawi et al., 1998; Wassink et al., 1999; Virgos et al., 2001). The 270C/T polymorphism was investigated in schizophrenia with both positive (Szekeres et al., 2003; Kunugi et al., 2001), and negative results (Galderisi et al., 2005). Negative results were also obtained in studies of anorexic and bulimic patients (Ribases et al., 2004). The two novel polymorphisms, 374A/T and 256G/A, were discovered by Ribases et al. (2003) in the screening analysis of the BDNF gene in patients with anorexia nervosa. However, no association analysis was performed. In this study, we investigated allelic distribution of the C-270T single nucleotide polymorphism (SNP) in the 5V noncoding region of the BDNF gene in a group of schizophrenic patients in comparison to a control group. We chose to investigate this polymorphism only because its
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localization and possible influence on changes in BDNF expression observed in schizophrenia.
2. Subjects and methods 2.1. Subjects The study was performed on 397 patients with schizophrenia (217 males with a mean age of 29.7 years, SD = 11.0 and 180 females with a mean age of 33.1 years, SD = 12.0). The patients were recruited from inpatients from the Wielkopolska region of western Poland treated in the Departments of Psychiatry of the Universities of Medical Sciences in Poznan and Bydgoszcz and the Psychiatric Hospital in Koscian. Consensus diagnosis according to DSM-IV and ICD-10 criteria was performed by at least two psychiatrists, for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID) (First et al., 1996). The control group consisted of 380 subjects (145 males with a mean age of 41.6 years, SD = 12.7 and 235 females with a mean age of 40.7 years, SD = 11.8). These controls were recruited from a group of blood donors, plus hospital staff and students from the Poznan University of Medical Sciences. They were not psychiatrically screened. The project was approved by the local ethics committee.
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6.2 Al at 37 8C with use of 0.7 units of HinfI restriction endonuclease (MBI Fermentas). Afterwards, the digestion products were separated on 3.5% basica LE agarose gel (Prona, Spain) with 90 V and visualised by ethidium bromide staining. Bands were compared to a pUC19DNA/MspI size marker and 50 bp DNA ladder (MBI Fermentas). The uncut PCR product was 223 bp. After RFLP analysis, the following alleles were observed: for the C allele, bands of 127 and 78 bp and for the T allele, bands of 127 and 63 bp. 2.3. Statistical analyses The Pearson’s chi-square (v 2) test and Fisher’s exact test were applied to test differences in the genotypic and allelic distribution, respectively, between the group of schizophrenic patients and the control subjects. Additionally, stepwise logistic regression analysis was performed for each diagnostic group, including the BDNF polymorphism and gender as covariates. All calculations were performed using the SPSS version 10 computer programme. A two-tailed type I error rate of 5% was chosen for analysis. Power analysis was performed using an on-line internet service provided by the UCLA Department of Statistics (http:// ebook.stat.ucla.edu/calculators/powercalc/binominal/ case-control/b-case-control-power.php).
2.2. Genotyping 3. Results DNA was extracted from 10 ml of EDTA anticoagulated whole blood, using the salting out method of Miller et al. (1988). A 223-basepair fragment of the BDNF gene was amplified by PCR reaction using the set of primers described by Kunugi et al. (2001) in a PTC-200 (MJ Research) thermal cycler. A 15 Al amplification mixture contained 150–300 ng of genomic DNA, 0.3 AM of each primer, 0.17 mM of each dNTP, 1.5 mM MgCl2, 75 mM Tris–HCl, 20 mM (NH4)2SO4, 0.01% Tween 20 and 0.4 U of Taq DNA polymerase (MBI Fermentas). The following PCR conditions were used: initial denaturation at 95 8C for 3 min. followed by 35 cycles with a profile of 94 8C for 30 s, 64 8C for 30 s, 72 8C for 30 s, and final elongation at 72 8C for 10 min. The PCR product (4.0 Al) was then digested overnight in a total volume of
The genotype distribution was in Hardy–Weinberg equilibrium for all the groups studied. The genotype and allele distributions for the patients with schizophrenia did not differ significantly from those in the control group ( p = 0.513 and p = 0.812, respectively) (Table 1). Also, when groups were divided according to gender, we did not find any significant differences in genotype and allele distribution (in the male group p = 0.151 for genotypes and p = 0.162 for alleles, respectively; in the female group p = 0.441 and p = 0.315, respectively). Only one female individual with a T/T genotype was present in the control group in our sample. However, it did not affect the genotype and allele frequency for the analyzed subgroup significantly.
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Table 1 Genotype distributions and allele frequencies of the BDNF C-270T polymorphism for patients with schizophrenia and the control group
Patients with schizophrenia Controls
Genotype C/C n (%)
Genotype C/T n (%)
Genotype T/T n (%)
Total genotypes n (%)
Allele C n (%)
Allele T n (%)
Total alleles n (%)
358 (90.2%)
39 (9.8%)
0 (0.0%)
397 (100%)
755 (95.1%)
39 (4.9%)
794 (100%)
346 (91.0%)
33 (8.7%)
1 (0.3%)
380 (100%)
725 (95.4%)
35 (4.6%)
760 (100%)
Patients with schizophrenia vs. controls—v 2 = 0.080, d.f. = 1, p = 0.513 for genotypes, p = 0.812 for alleles.
There was no association in logistic regression analysis between the analyzed BDNF polymorphism and schizophrenia (Wald test = 1.954, d.f. = 2, p = 0.617), after controlling for gender. The power to detect an association for relative risk, which in our sample was estimated as 1.75, was 77%.
4. Discussion In our study we did not find any association between the C-270T polymorphism in the BDNF gene and schizophrenia ( p = 0.513 for genotypes and p = 0.812 for alleles). We also did not find any sexspecific association. The functional significance of the C-270T substitution in the promoter region of BDNF is not clear. Changes in BDNF protein levels in the brain or serum of schizophrenic patients have been reported (Takahashi et al., 2000; Durany et al., 2001; Weickert et al., 2003), but there is no evidence that the C-270T polymorphism is responsible for such alterations in protein expression. Changes in BDNF expression were described in response to antipsychotic treatment (Angelucci et al., 2000; Linden et al., 2000; ChlanFourney et al., 2002) and to antidepressant therapy (Popoli et al., 2002; Coppell et al., 2003; Ivy et al., 2003). All these data make the BDNF gene a novel and promising target in association studies of schizophrenia, as well as in pharmacogenetic studies. Recent studies considering the C-270T polymorphism have included association analyses with schizophrenia, bipolar disorder, anorexia nervosa, bulimia nervosa and Alzheimer’s disease. Szekeres et al. (2003) found a strong association was found between heterozygous C/T genotype and T allele and a susceptibility to schizophrenia. Similar results were reported by Nanko et al. (2003) who found a weak, but significant excess of heterozygous C/T
genotype and the T allele and schizophrenia. However, Galderisi et al. (2005) found no differences in allele distribution between patients and controls. Analyses of association studies with other psychiatric disorders have shown different results. In their study of anorexia and bulimia, Ribases et al. (2004) detected an association between the C allele and weight loss and a high maxBMI in late age of onset with bulimia. In the same multinational study, allelic heterogeneity in distribution of the C-270T polymorphism was described. The T allele and heterozygous genotype were overrepresented only in a German sample, while in an Italian group allele C predominated. In a study of the C-270T polymorphism in Alzheimer’s disease in a German sample, a significant overrepresentation of the heterozygous C/T genotype was reported in these patients (Riemenschneider et al., 2002). The lack of association of the C-270T polymorphism with schizophrenia reported here is consistent with the recent study by Galderisi et al. (2005) who also did not detect an association of this polymorphism with schizophrenia. However, previous findings on this subject (Szekeres et al., 2003; Nanko et al., 2003) have reported an association between the T allele and the disease. This could be due to differences in the size of the samples analyzed (positive results: in Szekeres’s n = 101 and in Kunugi’s study n = 178; negative results in Galderisi’s n = 94 and n = 397 in our study). One should also consider the diversity of genotype and allele distribution between different populations which might be responsible for the differences in study results. Novel variants of BDNF gene were reported by Friedel et al. (2005) who screened the translated main exon of BDNF and identified three rare variants in German obese and underweight individuals: c.5C/T; c.273G/A; c.*137A/G. However, it is very unlikely
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