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Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

Molecular Psychiatry volume 12, pages 94–104 (2007)Cite this article

Abstract

Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P=0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P=0.00032), bipolar disorder (P=0.0011), and the combined case group (P=0.0017). This region includes the 5′ exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P>0.05). Region B contains a haplotype associated with both schizophrenia (P=0.00014), and the combined case group (P=0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P=0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P=0.024 and P=0.016, respectively). It spans a ∼136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3′ exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

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Acknowledgements

We are indebted to patients, their families and volunteers for their participation in this study. We would also like to thank Maura Walker and Margaret Van Beck for the collation of patient data. We thank Kirsty Millar, Helen Torrance, Susan Anderson, Alison Condie, John Beekman, Pat Malloy, Alan MacLean, Rosalind Launchbury, Sebastienne Buchanan and the Wellcome Trust CRF Genetics Core for their help in the preparation of the samples. We thank Illumina, San Diego, for SNP genotyping our samples and to Simon T Cooper for help in the preparation of this manuscript. This work was supported from grants from the Chief Scientists Office, the Scottish Executive; the Health Foundation, London; the Medical Research Council, UK and the Wellcome Trust.

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  1. Department of Medical Sciences, Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK

    P A Thomson, A Christoforou, S W Morris, E Adie, B S Pickard, D J Porteous & K L Evans

  2. Division of Psychiatry, Royal Edinburgh Hospital, Edinburgh, UK

    W J Muir & D H R Blackwood

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Thomson, P., Christoforou, A., Morris, S. et al. Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 12, 94–104 (2007). https://doi.org/10.1038/sj.mp.4001889

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