title: 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 case-control 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.
authors: Ctra. de l'Institut Pere Mata s/n, University Psychiatric Hospital, Pere Mata Institute, Reus, Tarragona, Spain.
authors: B
authors: B
authors: Roig
authors: C
authors: C
authors: Virgos
authors: N
authors: N
authors: Franco
authors: L
authors: L
authors: Martorell
authors: J
authors: J
authors: Valero
authors: J
authors: J
authors: Costas
authors: A
authors: A
authors: Carracedo
authors: A
authors: A
authors: Labad
authors: E
authors: E
authors: Vilella
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001216:Asparagine / Q000235:genetics; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D000070819:Discoidin Domain Receptor 1; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012559:Schizophrenia / Q000235:genetics*; D012694:Serine / Q000235:genetics; D014633:Valine / Q000235:genetics
chemical_list: D012694:Serine; D001216:Asparagine; D008715:Methionine; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D014633:Valine