1. ¹Medical Genetics Section, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK
2. ²MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
3. ³Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK

Correspondence: Dr A Christoforou, Medical Genetics, Centre of Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK. E-mail: a.christoforou@ed.ac.uk

⁴These authors contributed equally to this work.

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.

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

Received 27 October 2006; Revised 1 January 2007; Accepted 6 February 2007; Published online 24 April 2007.

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 (P0.0005) 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, P0.0003). These overlapping haplotypes fell into two regions. Within each of these four clusters, at least one globally significant haplotype withstood permutation testing (P_gp0.05). 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.