Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

B S Pickard, M P Malloy, A Christoforou, P A Thomson, K L Evans, S W Morris, M Hampson, D J Porteous, D H R Blackwood, W J Muir

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.

LanguageEnglish
Pages847-857
Number of pages11
JournalMolecular Psychiatry
Volume11
Issue number9
DOIs
Publication statusPublished - Sep 2006

Fingerprint

Kainic Acid Receptors
Glutamate Receptors
Bipolar Disorder
Cytogenetics
Schizophrenia
Haplotypes
Genes
Single Nucleotide Polymorphism
Psychiatry
Glutamic Acid
Odds Ratio
Ionotropic Glutamate Receptors
Kainic Acid
Learning Disorders
Genetic Association Studies
Synaptic Transmission
Intellectual Disability
Case-Control Studies
Population

Keywords

  • bipolar disorder
  • cells, cultured
  • Chromosomes, Human, Pair 2
  • DNA primers
  • exons
  • female
  • gene rearrangement
  • humans
  • in situ hybridization, fluorescence
  • intellectual disability
  • karyotyping
  • polymerase chain reaction
  • receptors, kainic acid
  • schizophrenia
  • translocation, genetic

Cite this

Pickard, B S ; Malloy, M P ; Christoforou, A ; Thomson, P A ; Evans, K L ; Morris, S W ; Hampson, M ; Porteous, D J ; Blackwood, D H R ; Muir, W J. / Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. In: Molecular Psychiatry. 2006 ; Vol. 11, No. 9. pp. 847-857.
@article{1bffdd5f0e404157b7c279f120079950,
title = "Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder",
abstract = "In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95{\%} CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95{\%} CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.",
keywords = "bipolar disorder, cells, cultured, Chromosomes, Human, Pair 2, DNA primers, exons, female, gene rearrangement, humans, in situ hybridization, fluorescence, intellectual disability, karyotyping, polymerase chain reaction, receptors, kainic acid, schizophrenia, translocation, genetic",
author = "Pickard, {B S} and Malloy, {M P} and A Christoforou and Thomson, {P A} and Evans, {K L} and Morris, {S W} and M Hampson and Porteous, {D J} and Blackwood, {D H R} and Muir, {W J}",
year = "2006",
month = "9",
doi = "10.1038/sj.mp.4001867",
language = "English",
volume = "11",
pages = "847--857",
journal = "Molecular Psychiatry",
issn = "1359-4184",
number = "9",

}

Pickard, BS, Malloy, MP, Christoforou, A, Thomson, PA, Evans, KL, Morris, SW, Hampson, M, Porteous, DJ, Blackwood, DHR & Muir, WJ 2006, 'Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder' Molecular Psychiatry, vol. 11, no. 9, pp. 847-857. https://doi.org/10.1038/sj.mp.4001867

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. / Pickard, B S; Malloy, M P; Christoforou, A; Thomson, P A; Evans, K L; Morris, S W; Hampson, M; Porteous, D J; Blackwood, D H R; Muir, W J.

In: Molecular Psychiatry, Vol. 11, No. 9, 09.2006, p. 847-857.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

AU - Pickard, B S

AU - Malloy, M P

AU - Christoforou, A

AU - Thomson, P A

AU - Evans, K L

AU - Morris, S W

AU - Hampson, M

AU - Porteous, D J

AU - Blackwood, D H R

AU - Muir, W J

PY - 2006/9

Y1 - 2006/9

N2 - In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.

AB - In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.

KW - bipolar disorder

KW - cells, cultured

KW - Chromosomes, Human, Pair 2

KW - DNA primers

KW - exons

KW - female

KW - gene rearrangement

KW - humans

KW - in situ hybridization, fluorescence

KW - intellectual disability

KW - karyotyping

KW - polymerase chain reaction

KW - receptors, kainic acid

KW - schizophrenia

KW - translocation, genetic

UR - http://www.nature.com/mp/

U2 - 10.1038/sj.mp.4001867

DO - 10.1038/sj.mp.4001867

M3 - Article

VL - 11

SP - 847

EP - 857

JO - Molecular Psychiatry

T2 - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 9

ER -