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Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Molecular Psychiatry volume 10, pages 366–374 (2005)Cite this article

Abstract

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population (‘HapICE’), and two haplotypes located in the 3′ end of NRG1 (all P<0.05). However, association was not detected with HapICE itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.

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Acknowledgements

We gratefully acknowledge the individuals who participated in this study. We thank Leslie Gaffney for graphics and manuscript preparation support, and Jill Platko and Skye Waggoner for technical assistance. This research was supported by NIMH Grants MH52618 and MH058693 to CNP, a NARSAD Young Investigator award to CNP, and a NARSAD Young Investigator award and a CIHR Postdoctoral Fellowship to TLP. MJD is a Pfizer Fellow in Computational Biology.

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Authors and Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    T L Petryshen, K A Aldinger, A R Tahl, G N Rockwell, N J Patterson & P Sklar

  2. Center for Neuropsychiatric Genetics, State University of New York (SUNY), Syracuse, NY, USA

    F A Middleton, C P Morley, H M Medeiros, C Carvalho, C N Pato & M T Pato

  3. Department of Psychiatry, State University of New York (SUNY), Syracuse, NY, USA

    F A Middleton, C P Morley, C N Pato & M T Pato

  4. Department of Neuroscience and Physiology, State University of New York (SUNY), Syracuse, NY, USA

    F A Middleton, L McGann & K L Gentile

  5. Whitehead Institute for Biomedical Research, Cambridge, MA, USA

    A Kirby, S Purcell & M J Daly

  6. Department of Psychiatry, Georgetown University, Washington, DC, USA

    H M Medeiros, C N Pato & M T Pato

  7. Psicologia Medica, Universidade de Coimbra, Coimbra, Portugal

    A Macedo, A Dourado, J Valente & M H Azevedo

  8. Psychiatry Service, Ponta Delgada, Azores, Portugal

    C P Ferreira

  9. Veterans Administration Medical Center, Washington, DC, USA

    C N Pato & M T Pato

  10. Department of Psychiatry, Harvard Medical School, and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Charlestown, MA, USA

    P Sklar

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  1. T L Petryshen
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Correspondence to P Sklar.

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Supplementary information accompanies the paper on Molecular Psychiatry website (http://www.nature.com.mp)

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Petryshen, T., Middleton, F., Kirby, A. et al. Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 10, 366–374 (2005). https://doi.org/10.1038/sj.mp.4001608

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