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Extreme population differences across Neuregulin 1 gene, with implications for association studies

Molecular Psychiatry volume 11, pages 66–75 (2006)Cite this article

Abstract

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme FST values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

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Acknowledgements

We thank Mònica Vallés, Universitat Pompeu Fabra, for technical assistance and Arcadi Navarro, Universitat Pompeu Fabra for reading of the manuscript and helpful discussion and suggestions. We also thank Hreinn Stefansson and Arnar Ingason from deCode, Iceland for constructive comments and providing unpublished information; and Howard Cann for his effort providing the CEPH samples.

The present study was supported by the Dirección General de Investigación, Ministerio de Educación y Ciencia, Spain (BFU2004-04208/BMC) and Direcció General de Recerca, Generalitat de Catalunya (2001SGR00285). MG received a fellowship from the International Graduate school of Catalunya (Generalitat de Catalunya).

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  1. Unitat de Biologia Evolutiva, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain

    M Gardner, A González-Neira, O Lao, F Calafell, J Bertranpetit & D Comas

  2. Departamento de Genética Humana, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

    A González-Neira

  3. Erasmus University Medical Center, Rotterdam, The Netherlands

    O Lao

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  1. M Gardner
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Gardner, M., González-Neira, A., Lao, O. et al. Extreme population differences across Neuregulin 1 gene, with implications for association studies. Mol Psychiatry 11, 66–75 (2006). https://doi.org/10.1038/sj.mp.4001749

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