Elsevier

Biological Psychiatry

Volume 70, Issue 1, 1 July 2011, Pages 35-42
Biological Psychiatry

Priority Communication
The Complement Control-Related Genes CSMD1 and CSMD2 Associate to Schizophrenia

https://doi.org/10.1016/j.biopsych.2011.01.030Get rights and content

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 case–control 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.

Section snippets

Patient Samples

The German case–control discovery sample consisted of patients with schizophrenia recruited from consecutive admissions to the inpatient units of the Central Institute of Mental Health in Mannheim, and the Department of Psychiatry at the University of Bonn. A description of this sample is given elsewhere (M.R., M.M., et al., unpublished data) (23). In brief, the sample includes genotypes from 466 patients and 1273 controls. Diagnoses were made according to DSM-IV criteria based on an Structured

Phase I: Mining of German Case–Control GWAS Data

Candidate genes were selected on the basis of our Gene Set Enrichment analysis of rat hippocampal HFS-LTP (17), as described in Methods and Materials. A knowledge-based selection was performed for genes that encode 1) complement-regulatory proteins acting from the step of initiation of the classical complement cascade (the C1Q complex) to the activation of C3, and 2) key regulators of antigen loading and presentation by MHC class I and MHC class II genes (Table S1 in Supplement 1). We examined

Discussion

Among the human RCAs that we selected for genetic association tests, the two homologous genes encoding the multiple domain proteins CSMD1 (chr. 8p23.2) and CSMD2 (chr. 1p35.1-34.3) are strongly associated with schizophrenia, suggesting that variants of RCAs have a significant effect on disease susceptibility. Notably, our candidate gene approach on a small number of markers resulted in genetic associations that in comparison with genome-wide analysis reaches the commonly accepted genome-wide

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