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

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

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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 (Pless than or equal to0.0005) 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, Pless than or equal to0.0003). These overlapping haplotypes fell into two regions. Within each of these four clusters, at least one globally significant haplotype withstood permutation testing (Pgpless than or equal to0.05). 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.
LanguageEnglish
Pages1011-1025
Number of pages15
JournalMolecular Psychiatry
Volume12
Early online date24 Apr 2007
DOIs
Publication statusPublished - 2007

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Bipolar Disorder
Haplotypes
Schizophrenia
Chromosomes
Single Nucleotide Polymorphism
HapMap Project
Principal Component Analysis
Genes
Phenotype

Keywords

  • bipolar disorder
  • genetics
  • schizophrenia
  • single nucleotide principal component analysis

Cite this

Christoforou, A., Le Hellard, S., Thomson, P. A., Morris, S. W., Tenesa, A., Pickard, B. S., ... Evans, K. L. (2007). Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia. Molecular Psychiatry, 12, 1011-1025. https://doi.org/10.1038/sj.mp.4002003
Christoforou, A. ; Le Hellard, S. ; Thomson, P. A. ; Morris, S. W. ; Tenesa, A. ; Pickard, B. S. ; Wray, N. R. ; Muir, W. J. ; Blackwood, D. H. ; Porteous, D. J. ; Evans, K. L. / Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia. In: Molecular Psychiatry. 2007 ; Vol. 12. pp. 1011-1025.
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Christoforou, A, Le Hellard, S, Thomson, PA, Morris, SW, Tenesa, A, Pickard, BS, Wray, NR, Muir, WJ, Blackwood, DH, Porteous, DJ & Evans, KL 2007, 'Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia' Molecular Psychiatry, vol. 12, pp. 1011-1025. https://doi.org/10.1038/sj.mp.4002003

Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia. / Christoforou, A.; Le Hellard, S.; Thomson, P. A.; Morris, S. W.; Tenesa, A.; Pickard, B. S.; Wray, N. R.; Muir, W. J.; Blackwood, D. H.; Porteous, D. J.; Evans, K. L.

In: Molecular Psychiatry, Vol. 12, 2007, p. 1011-1025.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association analysis of the chromosome 4p15–p16 candidate region for bipolar disorder and schizophrenia

AU - Christoforou, A.

AU - Le Hellard, S.

AU - Thomson, P. A.

AU - Morris, S. W.

AU - Tenesa, A.

AU - Pickard, B. S.

AU - Wray, N. R.

AU - Muir, W. J.

AU - Blackwood, D. H.

AU - Porteous, D. J.

AU - Evans, K. L.

PY - 2007

Y1 - 2007

N2 - 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 (Pless than or equal to0.0005) 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, Pless than or equal to0.0003). These overlapping haplotypes fell into two regions. Within each of these four clusters, at least one globally significant haplotype withstood permutation testing (Pgpless than or equal to0.05). 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.

AB - 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 (Pless than or equal to0.0005) 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, Pless than or equal to0.0003). These overlapping haplotypes fell into two regions. Within each of these four clusters, at least one globally significant haplotype withstood permutation testing (Pgpless than or equal to0.05). 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.

KW - bipolar disorder

KW - genetics

KW - schizophrenia

KW - single nucleotide principal component analysis

UR - http://www.ncbi.nlm.nih.gov/pubmed/17457313

U2 - 10.1038/sj.mp.4002003

DO - 10.1038/sj.mp.4002003

M3 - Article

VL - 12

SP - 1011

EP - 1025

JO - Molecular Psychiatry

T2 - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -