A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder

B S Pickard, H M Knight, R S Hamilton, D C Soares, R Walker, J K F Boyd, J Machell, K A McGhee, A Condie, D J Porteous, D St Clair, I Davis, D H R Blackwood, W J Muir

Research output: Contribution to journalArticle

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Abstract

Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3′ end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3′ untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.
LanguageEnglish
Pages14940-14945
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume105
Issue number39
DOIs
Publication statusPublished - 30 Sep 2008

Fingerprint

Glutamate Receptors
3' Untranslated Regions
Bipolar Disorder
Haplotypes
Genes
Case-Control Studies
Schizophrenia
Alleles
Ionotropic Glutamate Receptors
Kainic Acid Receptors
Kainic Acid
Learning Disorders
Chromosome Aberrations
Intellectual Disability
RNA
Messenger RNA

Keywords

  • case-control association
  • indel
  • RNA structure
  • hippocampus
  • mental illness
  • pharmacology

Cite this

Pickard, B S ; Knight, H M ; Hamilton, R S ; Soares, D C ; Walker, R ; Boyd, J K F ; Machell, J ; McGhee, K A ; Condie, A ; Porteous, D J ; St Clair, D ; Davis, I ; Blackwood, D H R ; Muir, W J. / A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. In: Proceedings of the National Academy of Sciences . 2008 ; Vol. 105, No. 39. pp. 14940-14945.
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Pickard, BS, Knight, HM, Hamilton, RS, Soares, DC, Walker, R, Boyd, JKF, Machell, J, McGhee, KA, Condie, A, Porteous, DJ, St Clair, D, Davis, I, Blackwood, DHR & Muir, WJ 2008, 'A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder' Proceedings of the National Academy of Sciences , vol. 105, no. 39, pp. 14940-14945. https://doi.org/10.1073/pnas.0800643105

A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. / Pickard, B S; Knight, H M; Hamilton, R S; Soares, D C; Walker, R; Boyd, J K F; Machell, J; McGhee, K A; Condie, A; Porteous, D J; St Clair, D; Davis, I; Blackwood, D H R; Muir, W J.

In: Proceedings of the National Academy of Sciences , Vol. 105, No. 39, 30.09.2008, p. 14940-14945.

Research output: Contribution to journalArticle

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T1 - A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder

AU - Pickard, B S

AU - Knight, H M

AU - Hamilton, R S

AU - Soares, D C

AU - Walker, R

AU - Boyd, J K F

AU - Machell, J

AU - McGhee, K A

AU - Condie, A

AU - Porteous, D J

AU - St Clair, D

AU - Davis, I

AU - Blackwood, D H R

AU - Muir, W J

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N2 - Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3′ end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3′ untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.

AB - Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3′ end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3′ untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.

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KW - RNA structure

KW - hippocampus

KW - mental illness

KW - pharmacology

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JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

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