The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia

Bjarte Håvik; Stephanie Le Hellard; Marcella Rietschel; Helle Lybæk; Srdjan Djurovic; Manuel Mattheisen; Thomas W. Mhleisen; Franziska Degenhardt; Lutz Priebe; Wolfgang Maier; Rene Breuer; Thomas G. Schulze; Ingrid Agartz; Ingrid Melle; Thomas Hansen; Clive R. Bramham; Markus M. Nthen; Beth Stevens; Thomas Werge; Ole A. Andreassen; Sven Cichon; Vidar M. Steen

doi:10.1016/j.biopsych.2011.01.030

The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia

Bjarte Håvik, Stephanie Le Hellard, Marcella Rietschel, Helle Lybæk, Srdjan Djurovic, Manuel Mattheisen, Thomas W. Mhleisen, Franziska Degenhardt, Lutz Priebe, Wolfgang Maier, Rene Breuer, Thomas G. Schulze, Ingrid Agartz, Ingrid Melle, Thomas Hansen, Clive R. Bramham, Markus M. Nthen, Beth Stevens, Thomas Werge, Ole A. AndreassenSven Cichon, Vidar M. Steen

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

Abstract

Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. Methods: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish casecontrol samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. Results: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10^-8; odd ratio = .73, 95% confidence interval = .65.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. Conclusions: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.

Original language	English (US)
Pages (from-to)	35-42
Number of pages	8
Journal	Biological Psychiatry
Volume	70
Issue number	1
DOIs	https://doi.org/10.1016/j.biopsych.2011.01.030
State	Published - Jul 1 2011
Externally published	Yes

Keywords

Complement cascade
csmd1
csmd2
human leukocyte antigen (HLA)
immunity
schizophrenia

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2011.01.030

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Håvik, B., Le Hellard, S., Rietschel, M., Lybæk, H., Djurovic, S., Mattheisen, M., Mhleisen, T. W., Degenhardt, F., Priebe, L., Maier, W., Breuer, R., Schulze, T. G., Agartz, I., Melle, I., Hansen, T., Bramham, C. R., Nthen, M. M., Stevens, B., Werge, T., ... Steen, V. M. (2011). The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biological Psychiatry, 70(1), 35-42. https://doi.org/10.1016/j.biopsych.2011.01.030

Håvik, B, Le Hellard, S, Rietschel, M, Lybæk, H, Djurovic, S, Mattheisen, M, Mhleisen, TW, Degenhardt, F, Priebe, L, Maier, W, Breuer, R, Schulze, TG, Agartz, I, Melle, I, Hansen, T, Bramham, CR, Nthen, MM, Stevens, B, Werge, T, Andreassen, OA, Cichon, S & Steen, VM 2011, 'The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia', Biological Psychiatry, vol. 70, no. 1, pp. 35-42. https://doi.org/10.1016/j.biopsych.2011.01.030

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abstract = "Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. Methods: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish casecontrol samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. Results: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10-8; odd ratio = .73, 95% confidence interval = .65.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. Conclusions: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.",

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AU - Håvik, Bjarte

AU - Le Hellard, Stephanie

AU - Rietschel, Marcella

AU - Lybæk, Helle

AU - Djurovic, Srdjan

AU - Mattheisen, Manuel

AU - Mhleisen, Thomas W.

AU - Degenhardt, Franziska

AU - Priebe, Lutz

AU - Maier, Wolfgang

AU - Breuer, Rene

AU - Schulze, Thomas G.

AU - Agartz, Ingrid

AU - Melle, Ingrid

AU - Hansen, Thomas

AU - Bramham, Clive R.

AU - Nthen, Markus M.

AU - Stevens, Beth

AU - Werge, Thomas

AU - Andreassen, Ole A.

AU - Cichon, Sven

AU - Steen, Vidar M.

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. Methods: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish casecontrol samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. Results: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10-8; odd ratio = .73, 95% confidence interval = .65.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. Conclusions: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.

AB - Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. Methods: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish casecontrol samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. Results: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10-8; odd ratio = .73, 95% confidence interval = .65.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. Conclusions: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.

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The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia

Abstract

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