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

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.