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

Molecular Psychiatry volume 12, pages 833–841 (2007)Cite this article

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.

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Acknowledgements

We thank Lídia Figuera and Carme Arbos (BioBanc IRCIS, Reus, Spain), and María Torres and Inés Quintela (Centro Nacional de Genotipado, CeGen, Santiago de Compostela, Spain) for their technical assistance. This study was supported, in part, by Grants from the Spanish Ministry of Health (RETIC G03/184 and PI020498) and The Stanley Medical Research Institute (03R-392).

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Author notes

  1. C Virgos

    Present address: 5Current address: Analytical Development, Genentech Inc., South San Francisco, CA 94080, USA,

  2. B Roig and C Virgos: These authors contributed equally to the work.

Authors and Affiliations

  1. Ctra. de l'Institut Pere Mata s/n, University Psychiatric Hospital, Pere Mata Institute, Reus, Tarragona, Spain

    B Roig, C Virgos, N Franco, L Martorell, J Valero, A Labad & E Vilella

  2. Psychiatric Unit of the Faculty of Medicine and Health Sciences, Rovira i Virgili University, Reus, Tarragona, Spain

    B Roig, C Virgos, N Franco, L Martorell, J Valero, A Labad & E Vilella

  3. Genomic Medicine Group-USC, Fundación Pública Galega de Medicina Xenómica, University of Santiago Hospital Complex, Santiago de Compostela, Spain

    J Costas & A Carracedo

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  1. B Roig
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Correspondence to E Vilella.

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Roig, B., Virgos, C., Franco, N. et al. The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia. Mol Psychiatry 12, 833–841 (2007). https://doi.org/10.1038/sj.mp.4001995

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