Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia

Catherine Winchester, Hiromitsu Ohzeki, Demetrius Vouyiouklis, Rhiannon Thompson, Keiji Yamagami, John Norrie, Robert Hunter , Judith Pratt, Brian J Morris

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Schizophrenia is a debilitating psychiatric disease with a strong genetic contribution, potentially linked to altered glutamatergic function in brain regions such as the prefrontal cortex (PFC). Here, we report converging
evidence to support a functional candidate gene for schizophrenia. In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7—a kinase activated by glutamatergic activity.
While mice lacking one copy of the Map2k7 gene were overtly normal in a variety of behavioural tests, these mice showed a schizophrenia-like cognitive phenotype of impaired working memory. Additional support for MAP2K7 as a candidate gene came from a genetic association study. A substantial effect size (odds ratios:
∼1.9) was observed for a common variant in a cohort of case and control samples collected in the Glasgow area and also in a replication cohort of samples of Northern European descent (most significant P-value:3 3 1024). While some caution is warranted until these association data are further replicated, these resultsare the first to implicate the candidate gene MAP2K7 in genetic risk for schizophrenia. Complete sequencing of all MAP2K7 exons did not reveal any non-synonymous mutations. However, the MAP2K7 haplotype appeared to have functional effects, in that it influenced the level of expression of MAP2K7 mRNA in humanPFC. Taken together, the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia.
LanguageEnglish
Pages4910-4921
Number of pages12
JournalHuman Molecular Genetics
Volume21
Issue number22
DOIs
Publication statusPublished - 15 Nov 2012

Fingerprint

Schizophrenia
Genes
Prefrontal Cortex
JNK Mitogen-Activated Protein Kinases
Genetic Association Studies
Short-Term Memory
Haplotypes
Psychiatry
Exons
Phosphotransferases
Odds Ratio
Phenotype
Messenger RNA
Mutation
Brain

Keywords

  • glutamate
  • schizophrenia
  • working memory
  • cognition

Cite this

Winchester, C., Ohzeki, H., Vouyiouklis, D., Thompson, R., Yamagami, K., Norrie, J., ... Morris , B. J. (2012). Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. Human Molecular Genetics , 21(22), 4910-4921. https://doi.org/10.1093/hmg/dds331
Winchester, Catherine ; Ohzeki, Hiromitsu ; Vouyiouklis, Demetrius ; Thompson, Rhiannon ; Yamagami, Keiji ; Norrie, John ; Hunter , Robert ; Pratt, Judith ; Morris , Brian J . / Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. In: Human Molecular Genetics . 2012 ; Vol. 21, No. 22. pp. 4910-4921.
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Winchester, C, Ohzeki, H, Vouyiouklis, D, Thompson, R, Yamagami, K, Norrie, J, Hunter , R, Pratt, J & Morris , BJ 2012, 'Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia' Human Molecular Genetics , vol. 21, no. 22, pp. 4910-4921. https://doi.org/10.1093/hmg/dds331

Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. / Winchester, Catherine; Ohzeki, Hiromitsu; Vouyiouklis, Demetrius ; Thompson, Rhiannon; Yamagami, Keiji ; Norrie, John ; Hunter , Robert ; Pratt, Judith; Morris , Brian J .

In: Human Molecular Genetics , Vol. 21, No. 22, 15.11.2012, p. 4910-4921.

Research output: Contribution to journalArticle

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T1 - Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia

AU - Winchester, Catherine

AU - Ohzeki, Hiromitsu

AU - Vouyiouklis, Demetrius

AU - Thompson, Rhiannon

AU - Yamagami, Keiji

AU - Norrie, John

AU - Hunter , Robert

AU - Pratt, Judith

AU - Morris , Brian J

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N2 - Schizophrenia is a debilitating psychiatric disease with a strong genetic contribution, potentially linked to altered glutamatergic function in brain regions such as the prefrontal cortex (PFC). Here, we report convergingevidence to support a functional candidate gene for schizophrenia. In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7—a kinase activated by glutamatergic activity.While mice lacking one copy of the Map2k7 gene were overtly normal in a variety of behavioural tests, these mice showed a schizophrenia-like cognitive phenotype of impaired working memory. Additional support for MAP2K7 as a candidate gene came from a genetic association study. A substantial effect size (odds ratios:∼1.9) was observed for a common variant in a cohort of case and control samples collected in the Glasgow area and also in a replication cohort of samples of Northern European descent (most significant P-value:3 3 1024). While some caution is warranted until these association data are further replicated, these resultsare the first to implicate the candidate gene MAP2K7 in genetic risk for schizophrenia. Complete sequencing of all MAP2K7 exons did not reveal any non-synonymous mutations. However, the MAP2K7 haplotype appeared to have functional effects, in that it influenced the level of expression of MAP2K7 mRNA in humanPFC. Taken together, the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia.

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