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Kynurenine 3-monooxygenase (KMO) polymorphisms in schizophrenia: An association study
Schizophrenia Research 127 (2011) 270–272
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editor Kynurenine 3-monooxygenase (KMO) polymorphisms in schizophrenia: An association study
Dear Editors, Kynurenic acid (KYNA) is an endogenous tryptophanmetabolite found to be increased in the brain of patients with schizophrenia (Erhardt et al., 2009, Wonodi and Schwarcz, 2010). KYNA antagonizes both the N-methyl-D-aspartate receptor (NMDAR) and the α7* nicotinic receptor (Wonodi and Schwarcz, 2010). This unique receptor profile may account for both hypoglutamatergia and impairment in cholinergic signaling, conditions that are implicated in schizophrenia (Wonodi and Schwarcz, 2010). Formation of KYNA indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine (Moroni, 1999). Since pharmacological blockade of KMO is known to induce the synthesis of KYNA, a polymorphism of the gene encoding KMO might similarly shunt the metabolism of kynurenine towards KYNA. Notably, the KMO gene is located on 1q42, a chromosome region associated with schizophrenia (Ekelund et al., 2004, Hamshere et al., 2005). Here, we investigate a possible association between KMO variations and schizophrenia. The case–control samples (for details, see Jönsson et al., 2009) originate from the Scandinavian Collaboration on Psychiatric Etiology (SCOPE) and were collected in Denmark, Norway, and Sweden. Affected individuals diagnosed with schizophrenia (n = 734), schizoaffective disorder (n = 87), or schizophreniform disorder (n = 16), according to ICD-10 (DK) or DSM-III-R/DSM-IV (NO and SE), were compared to unrelated controls (n = 1473). The study was approved by the local Ethics Committees. All participants were of Caucasian origin and, in accordance with the Declaration of Helsinki, had given informed consent prior to inclusion into the study. Fifteen KMO single nucleotide polymorphisms (SNPs) spanning 60 kb from the 5′ near gene region to intron 15 were selected for genotyping, including at least two in each of the four haplotype blocks of the gene, representing a gene coverage of 79%. The Hardy–Weinberg (HW) equilibrium was tested in the control samples using Fisher's exact test. To account for possible population stratification, we included country as a confounder factor in the disease genotype and allele association analysis. Test for heterogeneity between countries was done by specifying country as a modifier in a 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.10.002
separate analysis. Power was estimated using simulations as previously described (Jönsson et al., 2009). No population stratification was evident between the healthy controls in the combined Scandinavian sample (FST = 0.001 ± 0.001; 95% bootstrap confidence interval). Neither in single marker analysis (Table 1), nor in haplotype analysis (data not shown), any of the 15 tested markers was associated with the disease. One SNP, rs2065799, showed evidence of association heterogeneity with respect to country of origin (Table 1): the minor allele was over-represented among Norwegian patients (p = 0.01; odds ratio (OR) = 2.3, 95% confidence interval (CI95) 1.2–4.4), but no association was found in the Danish or Swedish samples (p-values = 0.66 and 0.16, respectively). However, after adjustment for multiple testing the association between the marker rs2065799 and the disease in the Norwegian sample did not reach the threshold for global significance (p = 0.14). The present sample was well powered to detect nominally significant allele differences of modest effects: for an allele OR = 1.4 the power varied between 1 (minor allele frequency [MAF] 0.2) and 0.72 (MAF = 0.05). However, the power to detect an OR of 1.2 was limited for alleles with a MAF of 0.1 or lower (power b 0.45). The present analysis of the combined Scandinavian sample did not reveal any allele frequency difference between patients and healthy controls. Although one SNP (rs2065799) was nominally associated with psychotic disorders in the Norwegian sample, the strength of this relationship was not sufficient for global significance. These results are in analogy with previous findings in a Japanese population (Aoyama et al., 2006) and may indicate worldwide consensus. Although, we do not find support for KMO polymorphisms to confer major susceptibility to schizophrenia per se, epigenetic factors leading to altered expression and decreased KMO activity (Wonodi and Schwarcz, 2010) might be related to elevated brain KYNA in patients with schizophrenia (Erhardt et al., 2009, Wonodi and Schwarcz, 2010). Furthermore, beyond the activity of KMO, the synthesis of brain KYNA is also highly dependent on the availability of kynurenine, the immediate precursor of KYNA. As recent studies show that also kynurenine is elevated in patients with schizophrenia (Linderholm et al., 2010, Wonodi and Schwarcz, 2010), one may speculate that polymorphisms in genes encoding indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO), enzymes converting tryptophan to kynurenine, may partly account for the elevated levels of KYNA in schizophrenia.
Letter to the Editor
271
Table 1 Allele and genotype association between single nucleotide polymorphisms (SNPs) in kynurenine 3-monooxygenase gene (KMO) and schizophrenia. SNP
RS10926508 RS2992642 RS3014572 RS2050513 RS3014569 RS10926513 RS6661244 RS6689793 RS3007737 RS2065799 RS3765806 RS12139441 RS4660103 RS850678 RS1053230
Base (1/2)a A/G A/C T/C C/A T/C A/T C/T G/C C/T C/T C/G A/G G/A A/T C/T
MAFb
0.03 0.26 0.27 0.16 0.14 0.40 0.33 0.09 0.43 0.07 0.33 0.18 0.28 0.25 0.23
HWc (p-value) 0.30 0.89 0.39 0.18 1.00 0.78 1.00 0.15 0.46 0.13 0.28 0.42 0.56 0.37 0.46
Case/Ctrl
Test of association (p-value)
11
12
22
Allele
Countryd
Genotype
Countryd
785/1393 421/773 419/774 598/1036 620/1090 307/529 375/666 687/1222 255/486 713/1268 372/680 564/998 432/769 453/829 520/873
50/77 311/537 350/595 213/381 199/341 392/707 367/648 140/234 432/704 116/193 376/627 244/421 336/597 327/541 281/528
0/2 61/95 64/101 22/45 11/26 137/228 94/158 8/17 147/277 6/12 85/164 26/51 67/106 53/100 34/71
0.85 0.15 0.17 0.32 0.94 0.95 0.54 0.95 0.58 0.66 0.72 0.95 0.86 0.52 0.23
0.80 0.72 0.81 0.83 0.47 0.29 0.36 0.68 0.76 0.04* 0.98 0.52 0.88 0.25 0.45
0.68 0.35 0.39 0.59 0.77 0.69 0.82 0.88 0.23 0.49 0.53 0.83 0.78 0.49 0.48
0.73 0.80 0.71 0.85 0.71 0.30 0.57 0.88 0.69 0.03* 0.98 0.52 0.97 0.49 0.43
a
Major/Minor allele. Minor allele frequency in controls. Test of Hardy–Weinberg equilibrium. d Test of association heterogeneity. ⁎Indicate nominal significance (p b 0.05). b c
Role of funding source This study was financed by grants from the Hållstens Forskningsstiftelse, Swedish Brain Foundation, Svenska Läkaresällskapet, Karolinska Institutet, Torsten och Ragnar Söderbergs stiftelse, Swedish Medical Research Council, Söderström-Königska stiftelsen, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Copenhagen Hospital Corporation Research Fund, the Danish National Psychiatric Research Foundation, the Danish Agency for Science, Technology and Innovation (Centre for Pharmacogenetics) to Thomas Werge, the Research Council of Norway (147787, 167153), the Eastern Norway Health Authority (Helse Øst RHF 123/2004), Ullevål University Hospital, and University of Oslo to the TOP study, the Swedish Research Council (No. 529-2004-6488 (S.E), K2009-62X-07484-24-3 (G.E.), K200762X-15077-04-1 (I.A.), K2007-62X-15078-04-3 (E.G.J.), K2008-62P-2059701-3 (E.G.J.), 10909 (M.S.)), Wallenberg Foundation, and the HUBIN project. The funding sources had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors MH wrote the initial draft and coordinated the preparation of the manuscript. PS performed the statistical analyses. SE and LS participated in the study design. TW participated in the study design and contributed with data collection (DK sample). TH contributed with data collection (DK sample). JN participated in the clinical characterization (DK sample). SD participated in the study design and contributed with data collection (NO sample). IM participated in the study design, clinical characterization and contributed with data collection (NO sample). OAA participated in the study design and contributed with data collection (NO sample). HH, LT and IE participated in the study design and contributed with data collection (SE sample). GE participated in the study design. EGJ participated in the study design, clinical characterization and contributed with data collection (SE sample). MS participated in the study design. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgements We thank patients and controls for their participation and express our gratitude towards health professionals who facilitated our work. We thank Frank Dudbridge for advice on UNPHASED, and Agneta Gunnar, Alexandra Tylec, Monica Hellberg, and Kjerstin Lind for technical assistance. We also thank Kristina Larsson, Per Lundmark, Tomas Axelsson and Ann-Christine
Syvänen at the SNP Technology Platform for performing the genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and by the Knut and Alice Wallenberg Foundation.
References Aoyama, N., Takahashi, N., Saito, S., Maeno, N., Ishihara, R., Ji, X., Miura, H., Ikeda, M., Suzuki, T., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Yoshida, K., Iwata, N., Inada, T., Ozaki, N., 2006. Association study between kynurenine 3-monooxygenase gene and schizophrenia in the Japanese population. Genes Brain. Behav. 5 (4), 364–368. Ekelund, J., Hennah, W., Hiekkalinna, T., Parker, A., Meyer, J., Lonnqvist, J., Peltonen, L., 2004. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol. Psychiatry 9 (11), 1037–1041. Erhardt, S., Olsson, S.K., Engberg, G., 2009. Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 23 (2), 91–101. Hamshere, M.L., Bennett, P., Williams, N., Segurado, R., Cardno, A., Norton, N., Lambert, D., Williams, H., Kirov, G., Corvin, A., Holmans, P., Jones, L., Jones, I., Gill, M., O'Donovan, M.C., Owen, M.J., Craddock, N., 2005. Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. Arch. Gen. Psychiatry 62 (10), 1081–1088. Jönsson, E.G., Saetre, P., Vares, M., Andreou, D., Larsson, K., Timm, S., Rasmussen, H.B., Djurovic, S., Melle, I., Andreassen, O.A., Agartz, I., Werge, T., Hall, H., Terenius, L., 2009. DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology 59, 142–150. Linderholm, K.R., Skogh, E., Olsson, S.K., Dahl, M.L., Holtze, M., Engberg, G., Samuelsson, M., Erhardt, S., 2010. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr. Bull. DOI:10.1093/schbul/sbq086. Moroni, F., 1999. Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur. J. Pharmacol. 375 (1–3), 87–100. Wonodi, I., Schwarcz, R., 2010. Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia. Schizophr. Bull. 36 (2), 211–218.
Maria Holtze Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden Peter Saetre Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden
272
Letter to the Editor
Sophie Erhardt Lilly Schwieler Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden Thomas Werge Thomas Hansen Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark Jimmi Nielsen Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark Srdjan Djurovic TOP project, Division of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Oslo, Norway Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway Ingrid Melle Ole A. Andreassen TOP project, Division of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Oslo, Norway
Ingrid Agartz Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden Institute of Psychiatry, University of Oslo, Psykiatrisk institutt, Vinderen, Oslo, Norway Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway Göran Engberg Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden Erik G. Jönsson1 Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden Corresponding author. Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, R5:00, SE-171 76 Stockholm, Sweden. Tel.: +46 8 517 726 26; fax: +46 8 34 65 63. E-mail address: [email protected]. Martin Schalling1 Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden 17 October 2009
Håkan Hall Lars Terenius Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden
1
The last two authors contributed equally to this study.
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editor Kynurenine 3-monooxygenase (KMO) polymorphisms in schizophrenia: An association study
Dear Editors, Kynurenic acid (KYNA) is an endogenous tryptophanmetabolite found to be increased in the brain of patients with schizophrenia (Erhardt et al., 2009, Wonodi and Schwarcz, 2010). KYNA antagonizes both the N-methyl-D-aspartate receptor (NMDAR) and the α7* nicotinic receptor (Wonodi and Schwarcz, 2010). This unique receptor profile may account for both hypoglutamatergia and impairment in cholinergic signaling, conditions that are implicated in schizophrenia (Wonodi and Schwarcz, 2010). Formation of KYNA indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine (Moroni, 1999). Since pharmacological blockade of KMO is known to induce the synthesis of KYNA, a polymorphism of the gene encoding KMO might similarly shunt the metabolism of kynurenine towards KYNA. Notably, the KMO gene is located on 1q42, a chromosome region associated with schizophrenia (Ekelund et al., 2004, Hamshere et al., 2005). Here, we investigate a possible association between KMO variations and schizophrenia. The case–control samples (for details, see Jönsson et al., 2009) originate from the Scandinavian Collaboration on Psychiatric Etiology (SCOPE) and were collected in Denmark, Norway, and Sweden. Affected individuals diagnosed with schizophrenia (n = 734), schizoaffective disorder (n = 87), or schizophreniform disorder (n = 16), according to ICD-10 (DK) or DSM-III-R/DSM-IV (NO and SE), were compared to unrelated controls (n = 1473). The study was approved by the local Ethics Committees. All participants were of Caucasian origin and, in accordance with the Declaration of Helsinki, had given informed consent prior to inclusion into the study. Fifteen KMO single nucleotide polymorphisms (SNPs) spanning 60 kb from the 5′ near gene region to intron 15 were selected for genotyping, including at least two in each of the four haplotype blocks of the gene, representing a gene coverage of 79%. The Hardy–Weinberg (HW) equilibrium was tested in the control samples using Fisher's exact test. To account for possible population stratification, we included country as a confounder factor in the disease genotype and allele association analysis. Test for heterogeneity between countries was done by specifying country as a modifier in a 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.10.002
separate analysis. Power was estimated using simulations as previously described (Jönsson et al., 2009). No population stratification was evident between the healthy controls in the combined Scandinavian sample (FST = 0.001 ± 0.001; 95% bootstrap confidence interval). Neither in single marker analysis (Table 1), nor in haplotype analysis (data not shown), any of the 15 tested markers was associated with the disease. One SNP, rs2065799, showed evidence of association heterogeneity with respect to country of origin (Table 1): the minor allele was over-represented among Norwegian patients (p = 0.01; odds ratio (OR) = 2.3, 95% confidence interval (CI95) 1.2–4.4), but no association was found in the Danish or Swedish samples (p-values = 0.66 and 0.16, respectively). However, after adjustment for multiple testing the association between the marker rs2065799 and the disease in the Norwegian sample did not reach the threshold for global significance (p = 0.14). The present sample was well powered to detect nominally significant allele differences of modest effects: for an allele OR = 1.4 the power varied between 1 (minor allele frequency [MAF] 0.2) and 0.72 (MAF = 0.05). However, the power to detect an OR of 1.2 was limited for alleles with a MAF of 0.1 or lower (power b 0.45). The present analysis of the combined Scandinavian sample did not reveal any allele frequency difference between patients and healthy controls. Although one SNP (rs2065799) was nominally associated with psychotic disorders in the Norwegian sample, the strength of this relationship was not sufficient for global significance. These results are in analogy with previous findings in a Japanese population (Aoyama et al., 2006) and may indicate worldwide consensus. Although, we do not find support for KMO polymorphisms to confer major susceptibility to schizophrenia per se, epigenetic factors leading to altered expression and decreased KMO activity (Wonodi and Schwarcz, 2010) might be related to elevated brain KYNA in patients with schizophrenia (Erhardt et al., 2009, Wonodi and Schwarcz, 2010). Furthermore, beyond the activity of KMO, the synthesis of brain KYNA is also highly dependent on the availability of kynurenine, the immediate precursor of KYNA. As recent studies show that also kynurenine is elevated in patients with schizophrenia (Linderholm et al., 2010, Wonodi and Schwarcz, 2010), one may speculate that polymorphisms in genes encoding indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO), enzymes converting tryptophan to kynurenine, may partly account for the elevated levels of KYNA in schizophrenia.
Letter to the Editor
271
Table 1 Allele and genotype association between single nucleotide polymorphisms (SNPs) in kynurenine 3-monooxygenase gene (KMO) and schizophrenia. SNP
RS10926508 RS2992642 RS3014572 RS2050513 RS3014569 RS10926513 RS6661244 RS6689793 RS3007737 RS2065799 RS3765806 RS12139441 RS4660103 RS850678 RS1053230
Base (1/2)a A/G A/C T/C C/A T/C A/T C/T G/C C/T C/T C/G A/G G/A A/T C/T
MAFb
0.03 0.26 0.27 0.16 0.14 0.40 0.33 0.09 0.43 0.07 0.33 0.18 0.28 0.25 0.23
HWc (p-value) 0.30 0.89 0.39 0.18 1.00 0.78 1.00 0.15 0.46 0.13 0.28 0.42 0.56 0.37 0.46
Case/Ctrl
Test of association (p-value)
11
12
22
Allele
Countryd
Genotype
Countryd
785/1393 421/773 419/774 598/1036 620/1090 307/529 375/666 687/1222 255/486 713/1268 372/680 564/998 432/769 453/829 520/873
50/77 311/537 350/595 213/381 199/341 392/707 367/648 140/234 432/704 116/193 376/627 244/421 336/597 327/541 281/528
0/2 61/95 64/101 22/45 11/26 137/228 94/158 8/17 147/277 6/12 85/164 26/51 67/106 53/100 34/71
0.85 0.15 0.17 0.32 0.94 0.95 0.54 0.95 0.58 0.66 0.72 0.95 0.86 0.52 0.23
0.80 0.72 0.81 0.83 0.47 0.29 0.36 0.68 0.76 0.04* 0.98 0.52 0.88 0.25 0.45
0.68 0.35 0.39 0.59 0.77 0.69 0.82 0.88 0.23 0.49 0.53 0.83 0.78 0.49 0.48
0.73 0.80 0.71 0.85 0.71 0.30 0.57 0.88 0.69 0.03* 0.98 0.52 0.97 0.49 0.43
a
Major/Minor allele. Minor allele frequency in controls. Test of Hardy–Weinberg equilibrium. d Test of association heterogeneity. ⁎Indicate nominal significance (p b 0.05). b c
Role of funding source This study was financed by grants from the Hållstens Forskningsstiftelse, Swedish Brain Foundation, Svenska Läkaresällskapet, Karolinska Institutet, Torsten och Ragnar Söderbergs stiftelse, Swedish Medical Research Council, Söderström-Königska stiftelsen, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Copenhagen Hospital Corporation Research Fund, the Danish National Psychiatric Research Foundation, the Danish Agency for Science, Technology and Innovation (Centre for Pharmacogenetics) to Thomas Werge, the Research Council of Norway (147787, 167153), the Eastern Norway Health Authority (Helse Øst RHF 123/2004), Ullevål University Hospital, and University of Oslo to the TOP study, the Swedish Research Council (No. 529-2004-6488 (S.E), K2009-62X-07484-24-3 (G.E.), K200762X-15077-04-1 (I.A.), K2007-62X-15078-04-3 (E.G.J.), K2008-62P-2059701-3 (E.G.J.), 10909 (M.S.)), Wallenberg Foundation, and the HUBIN project. The funding sources had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors MH wrote the initial draft and coordinated the preparation of the manuscript. PS performed the statistical analyses. SE and LS participated in the study design. TW participated in the study design and contributed with data collection (DK sample). TH contributed with data collection (DK sample). JN participated in the clinical characterization (DK sample). SD participated in the study design and contributed with data collection (NO sample). IM participated in the study design, clinical characterization and contributed with data collection (NO sample). OAA participated in the study design and contributed with data collection (NO sample). HH, LT and IE participated in the study design and contributed with data collection (SE sample). GE participated in the study design. EGJ participated in the study design, clinical characterization and contributed with data collection (SE sample). MS participated in the study design. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgements We thank patients and controls for their participation and express our gratitude towards health professionals who facilitated our work. We thank Frank Dudbridge for advice on UNPHASED, and Agneta Gunnar, Alexandra Tylec, Monica Hellberg, and Kjerstin Lind for technical assistance. We also thank Kristina Larsson, Per Lundmark, Tomas Axelsson and Ann-Christine
Syvänen at the SNP Technology Platform for performing the genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and by the Knut and Alice Wallenberg Foundation.
References Aoyama, N., Takahashi, N., Saito, S., Maeno, N., Ishihara, R., Ji, X., Miura, H., Ikeda, M., Suzuki, T., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Yoshida, K., Iwata, N., Inada, T., Ozaki, N., 2006. Association study between kynurenine 3-monooxygenase gene and schizophrenia in the Japanese population. Genes Brain. Behav. 5 (4), 364–368. Ekelund, J., Hennah, W., Hiekkalinna, T., Parker, A., Meyer, J., Lonnqvist, J., Peltonen, L., 2004. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol. Psychiatry 9 (11), 1037–1041. Erhardt, S., Olsson, S.K., Engberg, G., 2009. Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 23 (2), 91–101. Hamshere, M.L., Bennett, P., Williams, N., Segurado, R., Cardno, A., Norton, N., Lambert, D., Williams, H., Kirov, G., Corvin, A., Holmans, P., Jones, L., Jones, I., Gill, M., O'Donovan, M.C., Owen, M.J., Craddock, N., 2005. Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. Arch. Gen. Psychiatry 62 (10), 1081–1088. Jönsson, E.G., Saetre, P., Vares, M., Andreou, D., Larsson, K., Timm, S., Rasmussen, H.B., Djurovic, S., Melle, I., Andreassen, O.A., Agartz, I., Werge, T., Hall, H., Terenius, L., 2009. DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology 59, 142–150. Linderholm, K.R., Skogh, E., Olsson, S.K., Dahl, M.L., Holtze, M., Engberg, G., Samuelsson, M., Erhardt, S., 2010. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr. Bull. DOI:10.1093/schbul/sbq086. Moroni, F., 1999. Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur. J. Pharmacol. 375 (1–3), 87–100. Wonodi, I., Schwarcz, R., 2010. Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia. Schizophr. Bull. 36 (2), 211–218.
Maria Holtze Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden Peter Saetre Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden
272
Letter to the Editor
Sophie Erhardt Lilly Schwieler Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden Thomas Werge Thomas Hansen Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark Jimmi Nielsen Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark Srdjan Djurovic TOP project, Division of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Oslo, Norway Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway Ingrid Melle Ole A. Andreassen TOP project, Division of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Oslo, Norway
Ingrid Agartz Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden Institute of Psychiatry, University of Oslo, Psykiatrisk institutt, Vinderen, Oslo, Norway Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway Göran Engberg Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden Erik G. Jönsson1 Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden Corresponding author. Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, R5:00, SE-171 76 Stockholm, Sweden. Tel.: +46 8 517 726 26; fax: +46 8 34 65 63. E-mail address: [email protected]. Martin Schalling1 Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden 17 October 2009
Håkan Hall Lars Terenius Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden
1
The last two authors contributed equally to this study.