The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

Abstract

Evidence suggests that myelin alterations could predispose to schizophrenia. Reduced expression of several myelin genes has been observed in schizophrenia patients. Recently, we identified the discoidin domain receptor 1 (DDR1; located at human chromosome 6p21.3) as a myelin gene in the mouse model and in a human oligodendroglial cell line. In the present study we screened for single nucleotide polymorphisms (SNPs) in the DNA from 100 schizophrenia patients. We identified a novel mutation within exon 10 that produces the amino-acid substitution N502S in the a-d isoforms, and M475V in the e isoform. However the frequency of the mutation (2%) was similar in schizophrenia patients and in control subjects. In a casecontrol assessment with 389 schizophrenic patients and 615 controls, we identified one SNP (SNP9, rs1049623) associated with schizophrenia (odds ratio = 1.44, 95% confidence interval: 1.15-1.79, adjusted P = 0.0016). This association was confirmed in haplotype analysis; the SNPs 9-10-11 (rs1049623, rs2267641 and rs2239518) haplotype remaining significant even after adjustment for multiple testing (adjusted P = 0.0136). Of note was a strong gender dependence in the association, that is, statistical significance restricted to men (adjusted P-value = 0.0002). Regression analysis of DDR1 mRNA expression in peripheral blood lymphocytes from schizophrenia patients showed that the presence of the G allele significantly decreased the relative number of mRNA copies in a dose-dependent manner (P = 0.003). These data suggest that the risk haplotype tags a cis-acting variant involved in the transcription regulation system of the gene. In conclusion, we propose the DDR1 as a new susceptibility gene for schizophrenia.

Linkage and association study of discoidin domain receptor 1 as a novel susceptibility gene for childhood IgA nephropathy

“…Even though previous studies contradict our finding (6)(7)(8)(9)(10)21,22), these studies nevertheless suggested that the DDR1 gene participates in the development and progression of diseases, such as, auto-inflammatory and renal diseases.…”

“…DDR1 is a possible susceptibility marker of diseases other than renal diseases, such as schizophrenia, ovarian cancer, juvenile oligoarthritis, hearing loss, Churg-Strauss syndrome, small cell lung carcinoma, and endometrial cancer (6)(7)(8)(9)(10)21,22). Notably, in one study on schizophrenia (9), in which rs1049623 was found to be a susceptibility marker, but this SNP was found to have no significance in the present study.…”

“…Messenger RNA (mRNA) expression of DDR1 is predominantly observed in epithelial cells, particularly those from the kidney, lung, gastrointestinal tract, and brain. However, little is known about the precise cellular distribution of DDR1 protein (1,3,(5)(6)(7)(8)(9)(10). After binding collagen, DDR1 is dimerized, and phosphorylated as tyrosine kinase, which leads to P38MAP/kinase activation, which means that it is the only collagen receptor known to display direct intracellular signaling activity.…”

Prolactin gene polymorphism (− 1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics

“…The gene that encodes prolactin (PRL) has been mapped to chromosome 6p21 (Evans, 1989;Owerbach et al, 1981). The 6p21 region has been identified as a susceptibility locus that harbors genes associated with schizophrenia (Roig et al, 2007;Schwab et al, 2003;Tochigi et al, 2004). A recent genome-wide analysis (Stefansson et al, 2009) also found that this region was significantly associated with schizophrenia.…”

MicroRNAs suggest a new mechanism for altered brain gene expression in schizophrenia

“…It seems counterintuitive that reduction in miR-219 appears to be responsible for hyperactivity in the acute dizocilpine paradigm but reducing miR-219 levels with antisense infusion reverses dizocilpine-induced hyperactivity. Despite these inconsistencies, it is important to note that the gene for miR-219 implicated by Kocerha et al (2) is located at 6p21, which is a putative susceptibility locus for schizophrenia (5).…”