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Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia

Molecular Psychiatry volume 12, pages 1011–1025 (2007)Cite this article

Abstract

Several independent linkage studies have identified chromosome 4p15–p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15–p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 Mb, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control individuals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (P⩽0.0005) at the global and individual haplotype test level and clustered in two regions. In region D, no individual SNPs were nominally significant, but multiple global and individual haplotypes were associated with BP and/or SCZ (region-wide threshold, P⩽0.0003). These overlapping haplotypes fell into two regions. Within each of these four clusters, at least one globally significant haplotype withstood permutation testing (Pgp⩽0.05). Five predicted genes were found within these associated regions, while Known/RefSeq genes, including KIAA0746 and PPARGC1A, mapped nearby. There were also nine other clusters within regions B and D with nominally significant haplotypes, but only at the individual haplotype level. KIAA0746, PPARGC1A, GPR125, CCKAR and DKFZp761B107 overlapped with these regions. This study has identified significant associations between BP and SCZ within the chromosome 4p linkage region, resulting in candidate regions worthy of further investigation.

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Acknowledgements

This work was supported from grants from the Chief Scientists Office, Scottish Executive; the Health Foundation, London; the Medical Research Council, UK and the Wellcome Trust. We thank the patients, their families and volunteers for their participation in this study. We thank Maura Walker, Margaret van Beck, Sally Roe and Susan Jackson 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 genotyping our samples. We thank Richard Adams for bioinformatics advice and Simon T Cooper for assistance in the preparation of the paper. Albert Tenesa acknowledges funding from Cancer Research UK.

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Author notes

  1. S Le Hellard

    Present address: 5Current address: Dr Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health Research Center, Section of Medical Genetics and Molecular Medicine, University of Bergen, Bergen, Norway.,

  2. N R Wray

    Present address: 6Current address: Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, QLD, Australia.,

  3. A Christoforou and S Le Hellard: These authors contributed equally to this work.

Authors and Affiliations

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

    A Christoforou, S Le Hellard, P A Thomson, S W Morris, B S Pickard, N R Wray, W J Muir, D H Blackwood, D J Porteous & K L Evans

  2. MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK

    A Tenesa

  3. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK

    W J Muir & D H Blackwood

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  1. A Christoforou
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Christoforou, A., Le Hellard, S., Thomson, P. et al. Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia. Mol Psychiatry 12, 1011–1025 (2007). https://doi.org/10.1038/sj.mp.4002003

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