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Several polymorphisms of the glucocorticoid receptor gene (NR3C1) and their associations with bipolar disorder
S74
Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
referred to the dentistry clinics of the same centres during the same time period (control group). The comparison was carried out by means of the Child Behaviour Checklist (CBCL), and the Child Global Assessment Scale (CGAS). Results: The mean scores of CBCL and CGAS were in normal range in both test and control groups but there were a significant difference in the mean scores of CBCL (t = 5.83, Pv b 0.000) and CGAS (t = 9.95, Pv b 0.000) between the two groups. Discussion: Major depressive disorder in parents may affect the psychiatric status of their offspring. Psychiatric evaluation of the offspring of depressive parents may be necessary. (Sponsor: Exir Pharmaceutical Company) Keywords: Major depressive disorder, Parents, Offspring, CBCL doi:10.1016/j.jad.2007.12.048
[P1.16] DNA methylation at 5-HT1A receptor promoter C(−1019)G polymorphism CpG sites in schizophrenia and depression M. Czesaka, J. Lua, C.A. Stockmeierb,c, M.C. Austinb, H.Y. Meltzerd, P.R. Albert*,a a
University of Ottawa, Canada b University of Mississippi Medical Center, USA c Case Western Reserve University, USA d Psychiatric Hospital at Vanderbilt, USA Disregulation of the serotonin (5-HT) system is strongly implicated in major depression and suicide, and the 5-HT1A receptor is a critical regulator of serotonergic activity. A C(− 1019)G 5-HT1A polymorphism was associated with depression and suicide (Lemonde et al., 2003), and blocks the function of transcription factors Deaf-1 and HES5. Since early lifetime, environmentdriven promoter methylation can establish lifelong changes in stress reactivity (Meaney and Szyf, 2005), and postnatal alteration in 5-HT1A receptor expression determines lifetime anxiety phenotype in mice (Gross et al., 2002), we hypothesized increased DNA methylation of the 5-HT1A polymorphism may increase risk for depression or suicide. Subjects: Retrospective psychiatric assessments identified control subjects (n = 12), or suicide victims with major depression (14), schizophrenia (12), or alcoholism (7), gathered with a modified SADS-L (Spitzer and
Endicott, 1978) and diagnoses made according to DSMIIIR. Brain tissue obtained at autopsy (Cleveland, OH) was matched for age, ethnicity and postmortem interval. Genomic DNA was isolated from cortical brain tissue and 5-HT1A polymorphism DNA isolated, amplified and analyzed for methylation using bisulfite modification procedure. Genotyping for 5-HT1A C(−1019)G was done using Taqman method. DNA methylation was examined at two CpG sites: C(− 1019) (POLY) and C(− 1007) (HES) in the Deaf-1/ HES5 elements. Methylation of POLY was low (b10%), detected in schizophrenia, alcoholism and controls. Methylation of HES ranged from 0–15%, with threefold greater methylation in schizophrenia vs. nonschizophrenia or depressed patient samples. Methylation of both sites was two-fold higher in C/C vs. C/G subjects, and not detected in G/G. In initial studies, Deaf-1 bound to methylated or non-methylated DNA element with similar affinity. In summary, both 5-HT1A polymorphism CpG sites were methylated and this may be associated with schizophrenia. The effect of DNA methylation on Deaf-1/HES5 function and 5-HT1A receptor expression will be addressed. Support from CIHR/CPRF/AstraZeneca/Rx&D, MH67996 and RR17701. Keywords: DNA methylation, Polymorphism, Depression, Transcription doi:10.1016/j.jad.2007.12.049
[P1.17] Several polymorphisms of the glucocorticoid receptor gene (NR3C1) and their associations with bipolar disorder A. Spijkera, E. Hoencamp*,a, E. van Rossumb, R. de Rijka, J. Haffmansa,c, M. Bloma a
Parnassia Bavo Groep, The Netherlands Erasmus Medical Center, The Netherlands c Leiden University Medical Cente, The Netherlands b
Introduction: In affective disorders, dysregulation of the hypothalamus–pituitary–adrenal (HPA)-axis is a frequently observed phenomenon. A diminished sensitivity to the negative feedback action of cortisol leads to compensatory hypercortisolemia. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR-gene (NR3C1) may be at the base of this altered reaction to stress and subsequently related to the development and course of affective disorders.
Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
Methods: The aim of our study is to elucidate associations between GR-gene polymorphisms and bipolar disorder (BD). In this study 245 patients with BD were interviewed to confirm diagnosis and subtype. Data on use of medication and sociodemographic data were also collected. From all patients, blood was collected in order to perform genotyping. The control group consisted of 532 healthy blood donors. Results: A trend was found towards a protective effect of the exon 9*-polymorphism (p = 0.14) and the TthIIIIpolymorphism (p b 0.05) in the manifestation of the disease. In patients with BD, exon 9*-polymorphismcarriers had significantly less (hypo-)manic episodes than noncarriers (p b 0.05). Discussion: The exon 9*-polymorphism and the TthIIII-polymorphism of the GR-gene may be associated with the clinical manifestation and course in patients with BD. Keywords: Bipolar, Glucocorticosteroid, Genotyping, HPA axis doi:10.1016/j.jad.2007.12.050
[P1.18] Interaction of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and folic acid levels in recurrent depression
S75
Methods: The present study was part of the Dutch DELTA study in remitted depressed (rMDD) patients with at least two depressive episodes in the past. MTHFR C677T genotype frequencies of rMDD patients (mean age 46.5 ± 9.6 years) with recurrent depressive disorder (n = 137) were compared with age- and sex-matched controls (HC; n = 70). Serum levels of folate, homocysteine and vitamin B6 and B12 were compared between groups. Results: We found no difference in prevalences of CC, CT and TT genotypes between both groups. Serum levels of folate, homocysteine and vitamins B6 and B12 were not significantly different between groups. In patients with the wild type (CC) was associated with lower folic acid levels compared to matched controls (p = .04), while folate levels were not significantly different between MDD and HC for other genotypes. Discussion: In contrast to healthy controls the CC genotype of the MTHFR C677T polymorphism mimics low folate status in rMDD-patients. This interaction is important as folic acid may have an antidepressant effect in itself, or as an adjunct to antidepressant drugs. The present study strengthens the accumulating evidence for the need 1) to control folic acid status in MDD and 2) to further analyse the impact of genotypes on folic acid metabolism in recurrent depression. Keywords: Recurrent depression, MDD-R, Folic acid, Vitamin B6/B12, Homocysteine, MTHFR C677T polymorphism doi:10.1016/j.jad.2007.12.051
A. Lok, J. Assies, M.W. Koeter, C.L. Bockting, I. Visser*, M. Moeton University of Amsterdam, The Netherlands Introduction: Low folate status and depression has been found in many studies of depressive patients. The evidence of folate being a factor in depression is strengthened by an emerging association of depression with a common polymorphism of a gene involved in the metabolism of folate: methylene tetrahydrofolate reductase (MTHFR). A thermolabile variant (677C N T) of the enzyme 5,10-methylenetetrahydrofolate reductase is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with recurrent depression. We measured the prevalence of MTHFR in relation to plasma levels of folate, vitamin B6 and B12 and homocysteine in recurrent Major Depressive Disorder (MDD-R) patients compared to a matched control group.
[P1.19] Sex differences in adolescent depressive symptoms: Monoaminergic genotype and stressful environment E. Comasco*, N. Nordquist Uppsala University, Sweden Stressful environment during adolescence is known to increase the risk of depression. Moreover gene variants exert a complex range of effects on human behavior and personality, with gender differences. The purpose of the study was to investigate if/how various kinds of stress and gene variants in the monoaminergic pathway act/interact to affect the vulnerability for depression in females and males. The study was performed on a normal population of 18 year-old adolescents from a Swedish county. A total
Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
referred to the dentistry clinics of the same centres during the same time period (control group). The comparison was carried out by means of the Child Behaviour Checklist (CBCL), and the Child Global Assessment Scale (CGAS). Results: The mean scores of CBCL and CGAS were in normal range in both test and control groups but there were a significant difference in the mean scores of CBCL (t = 5.83, Pv b 0.000) and CGAS (t = 9.95, Pv b 0.000) between the two groups. Discussion: Major depressive disorder in parents may affect the psychiatric status of their offspring. Psychiatric evaluation of the offspring of depressive parents may be necessary. (Sponsor: Exir Pharmaceutical Company) Keywords: Major depressive disorder, Parents, Offspring, CBCL doi:10.1016/j.jad.2007.12.048
[P1.16] DNA methylation at 5-HT1A receptor promoter C(−1019)G polymorphism CpG sites in schizophrenia and depression M. Czesaka, J. Lua, C.A. Stockmeierb,c, M.C. Austinb, H.Y. Meltzerd, P.R. Albert*,a a
University of Ottawa, Canada b University of Mississippi Medical Center, USA c Case Western Reserve University, USA d Psychiatric Hospital at Vanderbilt, USA Disregulation of the serotonin (5-HT) system is strongly implicated in major depression and suicide, and the 5-HT1A receptor is a critical regulator of serotonergic activity. A C(− 1019)G 5-HT1A polymorphism was associated with depression and suicide (Lemonde et al., 2003), and blocks the function of transcription factors Deaf-1 and HES5. Since early lifetime, environmentdriven promoter methylation can establish lifelong changes in stress reactivity (Meaney and Szyf, 2005), and postnatal alteration in 5-HT1A receptor expression determines lifetime anxiety phenotype in mice (Gross et al., 2002), we hypothesized increased DNA methylation of the 5-HT1A polymorphism may increase risk for depression or suicide. Subjects: Retrospective psychiatric assessments identified control subjects (n = 12), or suicide victims with major depression (14), schizophrenia (12), or alcoholism (7), gathered with a modified SADS-L (Spitzer and
Endicott, 1978) and diagnoses made according to DSMIIIR. Brain tissue obtained at autopsy (Cleveland, OH) was matched for age, ethnicity and postmortem interval. Genomic DNA was isolated from cortical brain tissue and 5-HT1A polymorphism DNA isolated, amplified and analyzed for methylation using bisulfite modification procedure. Genotyping for 5-HT1A C(−1019)G was done using Taqman method. DNA methylation was examined at two CpG sites: C(− 1019) (POLY) and C(− 1007) (HES) in the Deaf-1/ HES5 elements. Methylation of POLY was low (b10%), detected in schizophrenia, alcoholism and controls. Methylation of HES ranged from 0–15%, with threefold greater methylation in schizophrenia vs. nonschizophrenia or depressed patient samples. Methylation of both sites was two-fold higher in C/C vs. C/G subjects, and not detected in G/G. In initial studies, Deaf-1 bound to methylated or non-methylated DNA element with similar affinity. In summary, both 5-HT1A polymorphism CpG sites were methylated and this may be associated with schizophrenia. The effect of DNA methylation on Deaf-1/HES5 function and 5-HT1A receptor expression will be addressed. Support from CIHR/CPRF/AstraZeneca/Rx&D, MH67996 and RR17701. Keywords: DNA methylation, Polymorphism, Depression, Transcription doi:10.1016/j.jad.2007.12.049
[P1.17] Several polymorphisms of the glucocorticoid receptor gene (NR3C1) and their associations with bipolar disorder A. Spijkera, E. Hoencamp*,a, E. van Rossumb, R. de Rijka, J. Haffmansa,c, M. Bloma a
Parnassia Bavo Groep, The Netherlands Erasmus Medical Center, The Netherlands c Leiden University Medical Cente, The Netherlands b
Introduction: In affective disorders, dysregulation of the hypothalamus–pituitary–adrenal (HPA)-axis is a frequently observed phenomenon. A diminished sensitivity to the negative feedback action of cortisol leads to compensatory hypercortisolemia. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR-gene (NR3C1) may be at the base of this altered reaction to stress and subsequently related to the development and course of affective disorders.
Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
Methods: The aim of our study is to elucidate associations between GR-gene polymorphisms and bipolar disorder (BD). In this study 245 patients with BD were interviewed to confirm diagnosis and subtype. Data on use of medication and sociodemographic data were also collected. From all patients, blood was collected in order to perform genotyping. The control group consisted of 532 healthy blood donors. Results: A trend was found towards a protective effect of the exon 9*-polymorphism (p = 0.14) and the TthIIIIpolymorphism (p b 0.05) in the manifestation of the disease. In patients with BD, exon 9*-polymorphismcarriers had significantly less (hypo-)manic episodes than noncarriers (p b 0.05). Discussion: The exon 9*-polymorphism and the TthIIII-polymorphism of the GR-gene may be associated with the clinical manifestation and course in patients with BD. Keywords: Bipolar, Glucocorticosteroid, Genotyping, HPA axis doi:10.1016/j.jad.2007.12.050
[P1.18] Interaction of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and folic acid levels in recurrent depression
S75
Methods: The present study was part of the Dutch DELTA study in remitted depressed (rMDD) patients with at least two depressive episodes in the past. MTHFR C677T genotype frequencies of rMDD patients (mean age 46.5 ± 9.6 years) with recurrent depressive disorder (n = 137) were compared with age- and sex-matched controls (HC; n = 70). Serum levels of folate, homocysteine and vitamin B6 and B12 were compared between groups. Results: We found no difference in prevalences of CC, CT and TT genotypes between both groups. Serum levels of folate, homocysteine and vitamins B6 and B12 were not significantly different between groups. In patients with the wild type (CC) was associated with lower folic acid levels compared to matched controls (p = .04), while folate levels were not significantly different between MDD and HC for other genotypes. Discussion: In contrast to healthy controls the CC genotype of the MTHFR C677T polymorphism mimics low folate status in rMDD-patients. This interaction is important as folic acid may have an antidepressant effect in itself, or as an adjunct to antidepressant drugs. The present study strengthens the accumulating evidence for the need 1) to control folic acid status in MDD and 2) to further analyse the impact of genotypes on folic acid metabolism in recurrent depression. Keywords: Recurrent depression, MDD-R, Folic acid, Vitamin B6/B12, Homocysteine, MTHFR C677T polymorphism doi:10.1016/j.jad.2007.12.051
A. Lok, J. Assies, M.W. Koeter, C.L. Bockting, I. Visser*, M. Moeton University of Amsterdam, The Netherlands Introduction: Low folate status and depression has been found in many studies of depressive patients. The evidence of folate being a factor in depression is strengthened by an emerging association of depression with a common polymorphism of a gene involved in the metabolism of folate: methylene tetrahydrofolate reductase (MTHFR). A thermolabile variant (677C N T) of the enzyme 5,10-methylenetetrahydrofolate reductase is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with recurrent depression. We measured the prevalence of MTHFR in relation to plasma levels of folate, vitamin B6 and B12 and homocysteine in recurrent Major Depressive Disorder (MDD-R) patients compared to a matched control group.
[P1.19] Sex differences in adolescent depressive symptoms: Monoaminergic genotype and stressful environment E. Comasco*, N. Nordquist Uppsala University, Sweden Stressful environment during adolescence is known to increase the risk of depression. Moreover gene variants exert a complex range of effects on human behavior and personality, with gender differences. The purpose of the study was to investigate if/how various kinds of stress and gene variants in the monoaminergic pathway act/interact to affect the vulnerability for depression in females and males. The study was performed on a normal population of 18 year-old adolescents from a Swedish county. A total