- Email: [email protected]
No association between polymorphisms and haplotypes of the AVPR1b, CRHR1 and NR3C1 genes and depression with melancholic features in the course of bipolar disorder
Psychiatry Research 207 (2013) 140–142
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
No association between polymorphisms and haplotypes of the AVPR1b, CRHR1 and NR3C1 genes and depression with melancholic features in the course of bipolar disorder Anna Leszczyn´ska-Rodziewicz a,b,n, Aleksandra Szczepankiewicz b,c, Monika Dmitrzak-W˛eglarz b, Aleksandra Rajewska-Rager a, Maria Skibin´ska b, Joanna Hauser b a b c
Department of Adult Psychiatry, Poznan University of Medical Sciences, ul. Szpitalna 27/33; 60-572 Poznan, Poland Psychiatric Genetics Unit, Poznan University of Medical Sciences, ul. Szpitalna 27/33; 60-572 Poznan, Poland Laboratory of Molecular and Cell Biology, Department of Pulmonology, Pediatric Allergy and Clinical Immunology, Poznan University of Medical Sciences, Poland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 January 2012 Received in revised form 10 September 2012 Accepted 15 September 2012
The present study included 130 patients with melancholic depression in the course of bipolar disorder and 732 healthy controls. No association was found for alleles, genotypes, or haplotype analysis for NR3C1, AVPR1b, and CRHR1 genes and melancholic depression. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Melancholic depression Hypothalamic-pituitary-adrenal (HPA) axis Association
1. Introduction Depression is viewed as a stress-related disorder, suggesting a causal role for dysregulation of the hypothalamic–pituitary– adrenal (HPA) axis. A pattern of HPA dysfunction is likely due to insufficient inhibitory feedback control with hyper-secretion of corticotrophin releasing hormone (CRH) and possibly impaired corticosteroid receptor signalling. There is evidence that treatment of depression is accompanied and preceded by a gradual reduction in neuroendocrine abnormalities (Nikisch, 2009), suggesting that HPA dysfunction may be state-related. It has also been suggested that severe-melancholic types of depression may be due to hyperactivity of the HPA axis and hypersecretion of releasing CRH neurons (Gold and Chrousos, 2002). In clinical studies, plasma arginine vasopressin (AVP) concentrations have been found to be elevated, and also positively correlated with cortisol levels in depression (de Winter et al., 2003). It is suggested that vasopressinergic circuits other than those regulating the HPA axis are involved in generating depression-like behaviour (Mlynarik et al., 2007). The activation of the oxytocin
n Corresponding author at: Department of Adult Psychiatry, Poznan University of Medical Sciences, ul. Szpitalna 27/33; 60-572 Poznan, Poland. Tel.: þ48 61 8491 311; fax: þ 48 61 8480 111. E-mail address: [email protected] (A. Leszczyn´ska-Rodziewicz).
0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.09.025
(OXT) neurons has been connected with low appetite and weight loss, cardinal symptoms of the melancholic type of depression. Also, the OXT mRNA is increased in the melancholic type of depression compared with the non–melancholic one; the highest amount of OXT mRNA was found in melancholic depressed subjects with severe weight loss (up to 16 kg/year 1) (Bao et al., 2008; Meynen et al., 2007). Taking into consideration all those data, we hypothesised that genetic variations in the NR3C1, CRHR1 and AVPR1b genes might be one of the factors influencing dysfunction of the HPA axis and therefore altering risk for melancholic depression.
2. Methods The study was performed on a group of 130 patients with melancholic depression in the course of bipolar type I (BPI) disorder (39 males and 91 females) from the total group of 514 BPI patients who were living in the Wielkopolska region of Poland. The duration of illness in our group ranged from 1 to 54 years (mean=15 years, S.D.=11). The control group consisted of 712 healthy subjects (301 males and 411 females). Patients were recruited from inpatients, treated at the Department of Adult Psychiatry, Poznan University of Medical Sciences. Diagnosis was done based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria of melancholic depression. The diagnosis was established using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). The Controls were blood donors, but only 40% of them were psychiatrically screened. Both patients and controls were of Polish origin. The study was approved by the Bioethics Committee of Poznan University of Medical
´ ska-Rodziewicz et al. / Psychiatry Research 207 (2013) 140–142 A. Leszczyn
Table 1 Polymorphisms in GR (NR3C1) gene in melancholic depression compared to control group. rs41423247
CC
CG
GG
p
n
%
n
%
n
%
0 1
90 16
12.48 12.4
325 48
45.08 37.21
306 65
42.44 50.39
rs6195
CC n 637 109
% 88.6 85.83
CT n 82 18
% 11.4 14.17
n 0 0
% 0 0
AA n 73 7
% 10.28 5.43
AG n 266 51
% 37.46 39.53
GG n 371 71
% 52.25 55.04
CC n 19 4
% 2.66 3.13
CT n 171 26
% 23.9 20.31
TT n 525 98
% 73.43 76.56
AA n 179 24
% 25.25 18.75
AC n 351 67
% 49.51 52.34
CC n 179 37
% 25.25 28.91
AA n 68 6
% 9.88 4.72
AG n 263 51
% 38.23 40.16
GG n 357 70
% 51.89 55.12
% 73.03 78.29
AG n 176 27
% 24.34 20.93
GG n 19 1
% 25.66 18.75
AT n 352 67
% 49.09 52.34
TT n 181 37
0 1 rs10052957 0 1 rs6198 0 1 rs6191 0 1 rs258813 0 1
Table 2 Polymorphisms in AVPR1b gene in melancholic depression compared to control group. rs28536160
0 1 rs33388 0 1
AA n 528 101 AA n 184 24
CC
CT
TT
p
n
%
n
%
n
%
0.2
0 1
6 0
0.84 0
104 14
14.57 10.94
604 114
84.59 89.06
p
rs28373064
AA n 479 95
% 66.25 74.22
AG n 215 27
% 29.74 21.09
GG n 29 6
% 4.01 4.69
CC n 1 0
% 0.14 0
CG n 79 15
% 11.27 12.2
GG n 621 108
% 88.59 87.8
AA n 0 0
% 0 0
AG n 141 22
% 20.14 17.19
GG n 559 106
% 79.86 82.8
0.37
0 1
p
rs35369693
0.22
0 1
p
rs28632197
0.65 p
0 1
0.3 p 0.13 p 0.87 p 0.43
0-control, 1-melancholic patients.
0.26 p 0.17
Table 3 Polymorphisms of CRHR1 gene in melancholic depression compared to control group. rs4076452
rs6196
141
CC
CG
GG
p
p % 2.63 0.78
p % 25.24 28.91
n
%
n
%
n
%
0 1
17 2
2.35 1.56
230 37
31.77 28.91
477 89
65.88 69.53
rs12936511
CC n 645 120
% 89.46 92.31
CT n 73 9
% 10.12 6.92
TT n 3 1
% 0.42 0.77
CC n 567 102
% 78.53 79.07
CT n 151 26
% 20.91 20.16
TT n 4 1
% 0.55 0.78
CC n 552 100
% 76.9 78.13
CT n 155 26
% 21.6 20.31
TT n 10 2
% 1.39 1.56
CC n 506 85
% 70.28 65.89
CG n 197 41
% 27.36 31.78
GG n 17 3
% 2.36 2.33
AA n 129 19
% 17.77 14.73
AG n 355 68
% 48.9 52.7
GG n 242 42
% 33.3 32.56
AA n 112 16
% 15.89 12.7
AG n 221 36
% 31.35 28.57
GG n 372 74
% 52.77 58.7
AA n 160 30
% 22.25 23.44
AG n 361 74
% 50.21 57.8
GG n 198 24
% 27.54 18.75
CC n 503 84
% 70.55 65.63
CT n 203 44
% 28.47 34.38
TT n 7 0
% 0.98 0
0.27
0.23 0 1
0.6 p 0.4
0-control, 1-melancholic patients. rs4792887 Sciences. Written informed consent was obtained from each individual after the procedure had been explained in detail. The project was approved by the local ethics committee. Genotyping, statistical analysis and the list of single-nucleotide polymorphisms (SNPs) analysed and the ID numbers of TaqMan assays were as previously described in Leszczyn´ska-Rodziewicz et al., (2012). Quanto was applied to calculate power in the present study.
0 1 rs242950 0 1 rs878886
3. Results Genotype distributions for all studied polymorphisms were in accordance with Hardy–Weinberg equilibrium in both cases and control subjects (p40.05) except for the control group for rs10052957 polymorphism. Table 1 presents the distribution of genotypic and allelic frequencies of the analysed SNPs in patients and controls. Neither genotypes nor alleles were significantly associated with melancholic depression. In addition, haplotype analysis did not show significant association of any haplotype with melancholic depression (data not shown) (Tables 2 and 3).
4. Discussion
0 1 rs173365 0 1 rs242937 0 1 rs110402 0 1 rs1694065
In our study we found no association between melancholic depression and polymorphisms in the NR3C1, AVPR1b and CRHR1 genes. In the last few years, SNPs in the NR3C1 gene have been investigated. The results of our study are inconsistent with the study performed by van Rossum et al. (2006), where BclI (rs41423247) and ER22/23EK (rs6189, rs6190) polymorphisms were associated with susceptibility to major depression. The
0 1
p 0.9 p 0.9 p 0.5 p 0.6 p 0.4 p 0.1 p 0.2
results of this study were also confirmed by van West et al. (2006). Also, Krishnamurthy et al. (2008) observed a potential role of Bc1I SNP in the pathogenesis of depression. Previously we have
142
´ ska-Rodziewicz et al. / Psychiatry Research 207 (2013) 140–142 A. Leszczyn
reported the association between the rs1293651 polymorphism of CRHR1 gene and bipolar patients with psychotic features (Leszczyn´ska-Rodziewicz et al., 2012). Moreover, in the study performed by Szczepankiewicz et al. (2011) three polymorphisms (rs6198, rs6191 and rs33388) of the NR3C1-1 gene were found to be associated with major depressive disorder and the same polymorphisms were associated with the predominance of depressive episodes in the course of bipolar disorder. In this study, we did not find such an association, although in the group of melancholic patients 50 had a previous lifetime history of psychotic features. A possible explanation of our negative findings might be that different gene interactions are involved in the aetiology of melancholic features than in the aetiology of psychotic features, which may also include environmental interactions which were not taken into account in this study. In conclusion, our study showed negative results, taking into consideration the limitations including the following: small sample size of the patients group (n¼130), no possibility to investigate sex dimorphic associations in these genes due to insufficient statistical power and the fact that only ...had been screened for psychiatric disorders; thus, there is a risk of falsenegative results, or type II error. The effect size of analysed SNPs is rather low (due to small odds ratios) and therefore in the present study we have limited capability to detect such an association. There is no medium-high effect of the studied polymorphisms in the NR3C1, AVPR1b and CRHR1 genes on susceptibility for melancholic depression in the course of bipolar illness, assuming the absence of confounding by underlying population stratification or gene– environment interactions.
Acknowledgement This study was supported by the Polish Ministry of Science and Higher Education, grant no N N402 243835.
References Bao, A., Meynen, G., Swaab, D., 2008. The stress system in depression and neurodegeneration: focus on human hypothalamus. Brain Research Reviews 57, 531–553. de Winter, R.F., van Hemert, A.M., DeRijk, R.H., Zwinderman, K.H., FrankhuijzenSierevogel, A.C., Wiegant, V.M., Goekoop, J.G., 2003. Anxious-retarded depression: relation with plasma vasopressin and cortisol. Neuropsychopharmacology 28 (1), 140–147. Gold, P., Chrousos, G., 2002. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Molecular Psychiatry 7, 254–275. Krishnamurthy, P., Romagni, P., Torvik, S., Gold, P.W., Charney, D.S., DeteraWadleigh, S., Cizza, G., P.O.W.E.R. (Premenopausal, Osteoporosis Women, Alendronate, Depression) Study Group, 2008. Glucocorticoid receptor polymorphisms in premenopausal women with major depression. Hormone and Metabolic Research 40, 194–198. Leszczyn´ska-Rodziewicz, A., Szczepankiewicz, A., Dmitrzak-W˛eglarz, M., Skibin´ska, M., Hauser, J., 2012 May. Association between functional polymorphism of the AVPR1b gene and polymorphism rs1293651 of the CRHR1 gene and bipolar disorder with psychotic features. Journal of Affective Disorders 138 (3), 490–493. Meynen, G., Unmehopa, U.A., Hoffman, M., Swaab, D., Hoogendijk, 2007. Hypothalamic oxytocin mRNA expression and melancholic depression. Molecular Psychiatry 12, 118–119. Mlynarik, M., Zelena, D., Bagdy, G., Makara, G.B., Jezova, D., 2007 Mar. Signs of attenuated depression-like behavior in vasopressin deficient Brattleboro rats. Hormones and Behavior 51 (3), 395–405. Nikisch, G., 2009. Involvement and role of antidepressant drugs of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor function. Neuro-endocrinology Letters 30 (1), 11–16. Szczepankiewicz, A., Leszczyn´ska-Rodziewicz, A., Pawlak, J., Rajewska-Rager, A., Dmitrzak-Weglarz, M., Wilkosc, M., Skibinska, M., Hauser, J., 2011. Glucocorticoid receptor polymorphism is associated with major depression and predominance of depression in the course of bipolar disorder. Journal of Affective Disorders 134, 138–144. van Rossum, E.F., Binder, E.B., Majer, M., Koper, J.W., Ising, M., Modell, S., Salyakina, D., Lamberts, S.W., Holsboer, F., 2006. Polymorphisms of the glucocorticoid receptor gene and major depression. Biological Psychiatry 59 (8), 681–688. van West, D., Van Den Eede, F., Del-Favero, J., Souery, D., Norrback, K.F., Van Duijn, C., Sluijs, S., Adolfsson, R., Mendlewicz, J., Deboutte, D., Van Broeckhoven, C., Claes, S., 2006. Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. Neuropsychopharmacology 31 (3), 620–627.
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
No association between polymorphisms and haplotypes of the AVPR1b, CRHR1 and NR3C1 genes and depression with melancholic features in the course of bipolar disorder Anna Leszczyn´ska-Rodziewicz a,b,n, Aleksandra Szczepankiewicz b,c, Monika Dmitrzak-W˛eglarz b, Aleksandra Rajewska-Rager a, Maria Skibin´ska b, Joanna Hauser b a b c
Department of Adult Psychiatry, Poznan University of Medical Sciences, ul. Szpitalna 27/33; 60-572 Poznan, Poland Psychiatric Genetics Unit, Poznan University of Medical Sciences, ul. Szpitalna 27/33; 60-572 Poznan, Poland Laboratory of Molecular and Cell Biology, Department of Pulmonology, Pediatric Allergy and Clinical Immunology, Poznan University of Medical Sciences, Poland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 January 2012 Received in revised form 10 September 2012 Accepted 15 September 2012
The present study included 130 patients with melancholic depression in the course of bipolar disorder and 732 healthy controls. No association was found for alleles, genotypes, or haplotype analysis for NR3C1, AVPR1b, and CRHR1 genes and melancholic depression. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Melancholic depression Hypothalamic-pituitary-adrenal (HPA) axis Association
1. Introduction Depression is viewed as a stress-related disorder, suggesting a causal role for dysregulation of the hypothalamic–pituitary– adrenal (HPA) axis. A pattern of HPA dysfunction is likely due to insufficient inhibitory feedback control with hyper-secretion of corticotrophin releasing hormone (CRH) and possibly impaired corticosteroid receptor signalling. There is evidence that treatment of depression is accompanied and preceded by a gradual reduction in neuroendocrine abnormalities (Nikisch, 2009), suggesting that HPA dysfunction may be state-related. It has also been suggested that severe-melancholic types of depression may be due to hyperactivity of the HPA axis and hypersecretion of releasing CRH neurons (Gold and Chrousos, 2002). In clinical studies, plasma arginine vasopressin (AVP) concentrations have been found to be elevated, and also positively correlated with cortisol levels in depression (de Winter et al., 2003). It is suggested that vasopressinergic circuits other than those regulating the HPA axis are involved in generating depression-like behaviour (Mlynarik et al., 2007). The activation of the oxytocin
n Corresponding author at: Department of Adult Psychiatry, Poznan University of Medical Sciences, ul. Szpitalna 27/33; 60-572 Poznan, Poland. Tel.: þ48 61 8491 311; fax: þ 48 61 8480 111. E-mail address: [email protected] (A. Leszczyn´ska-Rodziewicz).
0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.09.025
(OXT) neurons has been connected with low appetite and weight loss, cardinal symptoms of the melancholic type of depression. Also, the OXT mRNA is increased in the melancholic type of depression compared with the non–melancholic one; the highest amount of OXT mRNA was found in melancholic depressed subjects with severe weight loss (up to 16 kg/year 1) (Bao et al., 2008; Meynen et al., 2007). Taking into consideration all those data, we hypothesised that genetic variations in the NR3C1, CRHR1 and AVPR1b genes might be one of the factors influencing dysfunction of the HPA axis and therefore altering risk for melancholic depression.
2. Methods The study was performed on a group of 130 patients with melancholic depression in the course of bipolar type I (BPI) disorder (39 males and 91 females) from the total group of 514 BPI patients who were living in the Wielkopolska region of Poland. The duration of illness in our group ranged from 1 to 54 years (mean=15 years, S.D.=11). The control group consisted of 712 healthy subjects (301 males and 411 females). Patients were recruited from inpatients, treated at the Department of Adult Psychiatry, Poznan University of Medical Sciences. Diagnosis was done based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria of melancholic depression. The diagnosis was established using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). The Controls were blood donors, but only 40% of them were psychiatrically screened. Both patients and controls were of Polish origin. The study was approved by the Bioethics Committee of Poznan University of Medical
´ ska-Rodziewicz et al. / Psychiatry Research 207 (2013) 140–142 A. Leszczyn
Table 1 Polymorphisms in GR (NR3C1) gene in melancholic depression compared to control group. rs41423247
CC
CG
GG
p
n
%
n
%
n
%
0 1
90 16
12.48 12.4
325 48
45.08 37.21
306 65
42.44 50.39
rs6195
CC n 637 109
% 88.6 85.83
CT n 82 18
% 11.4 14.17
n 0 0
% 0 0
AA n 73 7
% 10.28 5.43
AG n 266 51
% 37.46 39.53
GG n 371 71
% 52.25 55.04
CC n 19 4
% 2.66 3.13
CT n 171 26
% 23.9 20.31
TT n 525 98
% 73.43 76.56
AA n 179 24
% 25.25 18.75
AC n 351 67
% 49.51 52.34
CC n 179 37
% 25.25 28.91
AA n 68 6
% 9.88 4.72
AG n 263 51
% 38.23 40.16
GG n 357 70
% 51.89 55.12
% 73.03 78.29
AG n 176 27
% 24.34 20.93
GG n 19 1
% 25.66 18.75
AT n 352 67
% 49.09 52.34
TT n 181 37
0 1 rs10052957 0 1 rs6198 0 1 rs6191 0 1 rs258813 0 1
Table 2 Polymorphisms in AVPR1b gene in melancholic depression compared to control group. rs28536160
0 1 rs33388 0 1
AA n 528 101 AA n 184 24
CC
CT
TT
p
n
%
n
%
n
%
0.2
0 1
6 0
0.84 0
104 14
14.57 10.94
604 114
84.59 89.06
p
rs28373064
AA n 479 95
% 66.25 74.22
AG n 215 27
% 29.74 21.09
GG n 29 6
% 4.01 4.69
CC n 1 0
% 0.14 0
CG n 79 15
% 11.27 12.2
GG n 621 108
% 88.59 87.8
AA n 0 0
% 0 0
AG n 141 22
% 20.14 17.19
GG n 559 106
% 79.86 82.8
0.37
0 1
p
rs35369693
0.22
0 1
p
rs28632197
0.65 p
0 1
0.3 p 0.13 p 0.87 p 0.43
0-control, 1-melancholic patients.
0.26 p 0.17
Table 3 Polymorphisms of CRHR1 gene in melancholic depression compared to control group. rs4076452
rs6196
141
CC
CG
GG
p
p % 2.63 0.78
p % 25.24 28.91
n
%
n
%
n
%
0 1
17 2
2.35 1.56
230 37
31.77 28.91
477 89
65.88 69.53
rs12936511
CC n 645 120
% 89.46 92.31
CT n 73 9
% 10.12 6.92
TT n 3 1
% 0.42 0.77
CC n 567 102
% 78.53 79.07
CT n 151 26
% 20.91 20.16
TT n 4 1
% 0.55 0.78
CC n 552 100
% 76.9 78.13
CT n 155 26
% 21.6 20.31
TT n 10 2
% 1.39 1.56
CC n 506 85
% 70.28 65.89
CG n 197 41
% 27.36 31.78
GG n 17 3
% 2.36 2.33
AA n 129 19
% 17.77 14.73
AG n 355 68
% 48.9 52.7
GG n 242 42
% 33.3 32.56
AA n 112 16
% 15.89 12.7
AG n 221 36
% 31.35 28.57
GG n 372 74
% 52.77 58.7
AA n 160 30
% 22.25 23.44
AG n 361 74
% 50.21 57.8
GG n 198 24
% 27.54 18.75
CC n 503 84
% 70.55 65.63
CT n 203 44
% 28.47 34.38
TT n 7 0
% 0.98 0
0.27
0.23 0 1
0.6 p 0.4
0-control, 1-melancholic patients. rs4792887 Sciences. Written informed consent was obtained from each individual after the procedure had been explained in detail. The project was approved by the local ethics committee. Genotyping, statistical analysis and the list of single-nucleotide polymorphisms (SNPs) analysed and the ID numbers of TaqMan assays were as previously described in Leszczyn´ska-Rodziewicz et al., (2012). Quanto was applied to calculate power in the present study.
0 1 rs242950 0 1 rs878886
3. Results Genotype distributions for all studied polymorphisms were in accordance with Hardy–Weinberg equilibrium in both cases and control subjects (p40.05) except for the control group for rs10052957 polymorphism. Table 1 presents the distribution of genotypic and allelic frequencies of the analysed SNPs in patients and controls. Neither genotypes nor alleles were significantly associated with melancholic depression. In addition, haplotype analysis did not show significant association of any haplotype with melancholic depression (data not shown) (Tables 2 and 3).
4. Discussion
0 1 rs173365 0 1 rs242937 0 1 rs110402 0 1 rs1694065
In our study we found no association between melancholic depression and polymorphisms in the NR3C1, AVPR1b and CRHR1 genes. In the last few years, SNPs in the NR3C1 gene have been investigated. The results of our study are inconsistent with the study performed by van Rossum et al. (2006), where BclI (rs41423247) and ER22/23EK (rs6189, rs6190) polymorphisms were associated with susceptibility to major depression. The
0 1
p 0.9 p 0.9 p 0.5 p 0.6 p 0.4 p 0.1 p 0.2
results of this study were also confirmed by van West et al. (2006). Also, Krishnamurthy et al. (2008) observed a potential role of Bc1I SNP in the pathogenesis of depression. Previously we have
142
´ ska-Rodziewicz et al. / Psychiatry Research 207 (2013) 140–142 A. Leszczyn
reported the association between the rs1293651 polymorphism of CRHR1 gene and bipolar patients with psychotic features (Leszczyn´ska-Rodziewicz et al., 2012). Moreover, in the study performed by Szczepankiewicz et al. (2011) three polymorphisms (rs6198, rs6191 and rs33388) of the NR3C1-1 gene were found to be associated with major depressive disorder and the same polymorphisms were associated with the predominance of depressive episodes in the course of bipolar disorder. In this study, we did not find such an association, although in the group of melancholic patients 50 had a previous lifetime history of psychotic features. A possible explanation of our negative findings might be that different gene interactions are involved in the aetiology of melancholic features than in the aetiology of psychotic features, which may also include environmental interactions which were not taken into account in this study. In conclusion, our study showed negative results, taking into consideration the limitations including the following: small sample size of the patients group (n¼130), no possibility to investigate sex dimorphic associations in these genes due to insufficient statistical power and the fact that only ...had been screened for psychiatric disorders; thus, there is a risk of falsenegative results, or type II error. The effect size of analysed SNPs is rather low (due to small odds ratios) and therefore in the present study we have limited capability to detect such an association. There is no medium-high effect of the studied polymorphisms in the NR3C1, AVPR1b and CRHR1 genes on susceptibility for melancholic depression in the course of bipolar illness, assuming the absence of confounding by underlying population stratification or gene– environment interactions.
Acknowledgement This study was supported by the Polish Ministry of Science and Higher Education, grant no N N402 243835.
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