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The effects of a neuregulin 1 variant on white matter density and integrity

Abstract

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T1-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

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References

  1. Kendell RE . The Role of Diagnosis in Psychiatry. Blackwell: Edinburgh, 1975.

    Google Scholar 

  2. McIntosh AM, Job DE, Moorhead TW, Harrison LK, Lawrie SM, Johnstone EC . White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives. Biol Psychiatry 2005; 58: 254–257.

    Article  PubMed  Google Scholar 

  3. Zhou S, Suzuki M, Hagino H, Takahashi T, Kawasaki Y, Nohara S et al. Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia. Biol Psychiatry 2003; 54: 427–436.

    Article  PubMed  Google Scholar 

  4. McIntosh AM, Job D, Moorhead TWJ, Harrison LK, Whalley HC, Johnstone EC et al. Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure. Am J Med Genet 2006; 141B: 76–83.

    Article  PubMed  Google Scholar 

  5. Guo AC, MacFall JR, Provenzale JM . Multiple sclerosis: diffusion tensor MR imaging for evaluation of normal-appearing white matter. Radiology 2002; 222: 729–736.

    Article  PubMed  Google Scholar 

  6. Shenton ME, Dickey CC, Frumin M, McCarley RW . A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 1–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sussmann JE, Lymer GKS, McKirdy J, Moorhead TWJ, Maniega SM, Job D et al. White matter abnormalities in bipolar disorder detected using diffusion tensor magnetic resonance imaging. (in review) 2007.

  8. Maniega SM, Lymer GKS, Bastin ME, Marjoram D, Job DE, Moorhead TWJ et al. A DT-MRI study of subjects at high genetic risk of schizophrenia. In review 2007.

  9. Craddock N, O'Donovan MC, Owen MJ . Genes for schizophrenia and bipolar disorder? Implications for psychiatric Nosology. Schizophr Bull 2006; 32: 9–16.

    Article  PubMed  Google Scholar 

  10. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Brynjolfsson J et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 185.

    Article  Google Scholar 

  11. Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 2003; 72: 83–87.

    Article  CAS  PubMed  Google Scholar 

  12. Thomson PA, Christoforou A, Morris SW, Adie E, Pickard BS, Porteous DJ et al. Association of neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 2007; 12: 94–104.

    Article  CAS  PubMed  Google Scholar 

  13. Green EK, Raybould R, MacGregor S, Gordon-Smith K, Heron J, Hyde S et al. Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Arch Gen Psychiatry 2005; 62: 642–648.

    Article  CAS  PubMed  Google Scholar 

  14. Li D, Collier DA, He L . Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 2006; 15: 1995–2002.

    Article  CAS  PubMed  Google Scholar 

  15. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 2006; 103: 6747–6752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tan W, Wang Y, Gold B, Chen J, Dean M, Harrison PJ et al. Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem 2007; 282: 24343–24351.

    Article  CAS  PubMed  Google Scholar 

  17. Hall J, Whalley HC, Job DE, Baig BJ, McIntosh AM, Evans KL et al. A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nat Neurosci 2006; 9: 1477–1478.

    Article  CAS  PubMed  Google Scholar 

  18. Stefanis NC, Trikalinos TA, Avramopoulos D, Smyrnis N, Evdokimidis I, Ntzani EE et al. Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. Biol Psychiatry 2007; 62: 784–792.

    Article  CAS  PubMed  Google Scholar 

  19. Friston KJ, Frith CD . Schizophrenia: a disconnection syndrome? Clin Neurosci 1995; 3: 89–97.

    CAS  PubMed  Google Scholar 

  20. Addington AM, Gornick MC, Shaw P, Seal J, Gogtay N, Greenstein D et al. Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories. Mol Psychiatry 2007; 12: 195–205.

    Article  CAS  PubMed  Google Scholar 

  21. Lopez-Bendito G, Cautinat A, Sanchez JA, Bielle F, Flames N, Garratt AN et al. Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell 2006; 125: 127–142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Corfas G, Roy K, Buxbaum J . Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 2004; 7: 575–580.

    Article  CAS  PubMed  Google Scholar 

  23. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS . A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001; 14 (Part 1): t-36.

    Google Scholar 

  24. Spencer MD, Moorhead TW, McIntosh AM, Stanfield AC, Muir WJ, Hoare P et al. Grey matter correlates of early psychotic symptoms in adolescents at enhanced risk of psychosis: a voxel-based study. Neuroimage 2007; 35: 1181–1191.

    Article  PubMed  Google Scholar 

  25. Moorhead TWJ, Job DE, Whalley HC, Sanderson TL, Johnstone EC, Lawrie SM . Voxel-based morphometry of comorbid schizophrenia and learning disability: analyses in normalized and native spaces using parametric and nonparametric statistical methods. Neuroimage 2004; 22: 188–202.

    Article  PubMed  Google Scholar 

  26. McIntosh AM, Job DE, Moorhead WJ, Harrison LK, Whalley HC, Johnstone EC et al. Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 76–83.

    Article  Google Scholar 

  27. Fletcher P, McKenna PJ, Friston KJ, Frith CD, Dolan RJ . Abnormal cingulate modulation of fronto-temporal connectivity in schizophrenia. Neuroimage 1999; 9: 337–342.

    Article  CAS  PubMed  Google Scholar 

  28. Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC . Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002; 51: 1008–1011.

    Article  PubMed  Google Scholar 

  29. Whalley HC, Simonotto E, Marshall I, Owens DG, Goddard NH, Johnstone EC et al. Functional disconnectivity in subjects at high genetic risk of schizophrenia. Brain 2005; 128 (Part 9): 2097–2108.

    Article  PubMed  Google Scholar 

  30. Harrison PJ, Law AJ . Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 2006; 60: 132–140.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all of the participants without whom this study would not have been possible. This study was supported by a Chief Scientist Office Project Grant (CZB/4/434) to AMM and colleagues, two MRC Programme Grants (G9226254/G9825423) to ECJ and colleagues, the Sir Mortimer and Theresa Sackler Foundation and two MRC Clinical Training Fellowships (G84/5699 to Dr McIntosh and G0600429 to Dr Hall). McIntosh is currently supported by the Health Foundation. We also thank the Scottish Funding Council Brain Imaging Research Centre and Wellcome Trust Clinical Research Facility for the image acquisition and genetic analyses respectively.

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Correspondence to A M McIntosh.

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McIntosh, A., Moorhead, T., Job, D. et al. The effects of a neuregulin 1 variant on white matter density and integrity. Mol Psychiatry 13, 1054–1059 (2008). https://doi.org/10.1038/sj.mp.4002103

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