Association of GRIN1 and GRIN2A-D With schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk

Ditte Demontis, Mette Nyegaard, Henriette N. Buttenschøn, Anne Hedemand, Carsten B. Pedersen, Jakob Grove, Tracey J. Flint, Merete Nordentoft, Thomas Werge, David M. Hougaard, Karina M. Sørensen, Robert H. Yolken, Ole Mors, Anders D. Børglum, Preben Bo Mortensen

Research output: Contribution to journalArticle

Abstract

N-methyl-D-aspartate (NMDA) receptors are very important for proper brain development and several lines of evidence support that hypofunction of the NMDA receptors are involved in the pathophysiology of schizophrenia. Gene variation and gene-environmental interactions involving the genes encoding the NMDA receptors are therefore likely to influence the risk of schizophrenia. The aim of this study was to determine (1) whether SNP variation in the genes (GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) encoding the NMDA receptor were associated with schizophrenia; (2) whether GRIN gene variation in the offspring interacted with maternal herpes simplex virus-2 (HSV-2) seropositivity during pregnancy influencing the risk of schizophrenia later in life. Individuals from three independently collected Danish case control samples were genotyped for 81 tagSNPs (in total 984 individuals diagnosed with schizophrenia and 1,500 control persons) and antibodies against maternal HSV-2 infection were measured in one of the samples (365 cases and 365 controls). Nine SNPs out of 30 in GRIN2B were significantly associated with schizophrenia. One SNP remained significant after Bonferroni correction (rs1806194, Pnominal=0.0008). Significant interaction between maternal HSV-2 seropositivity and GRIN2B genetic variation in the offspring were observed for seven SNPs and two remained significant after Bonferroni correction (rs1805539, Pnominal=0.0001 and rs1806205, Pnominal=0.0008). The significant associations and interactions were located at the 3' region of GRIN2B suggesting that genetic variation in this part of the gene may be involved in the pathophysiology of schizophrenia.

Original languageEnglish (US)
Pages (from-to)913-922
Number of pages10
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume156
Issue number8
DOIs
StatePublished - Dec 1 2011

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Keywords

  • GRIN2B
  • Gene-environment interaction
  • Herpes simplex virus-2
  • NMDA receptor
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Demontis, D., Nyegaard, M., Buttenschøn, H. N., Hedemand, A., Pedersen, C. B., Grove, J., Flint, T. J., Nordentoft, M., Werge, T., Hougaard, D. M., Sørensen, K. M., Yolken, R. H., Mors, O., Børglum, A. D., & Mortensen, P. B. (2011). Association of GRIN1 and GRIN2A-D With schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 156(8), 913-922. https://doi.org/10.1002/ajmg.b.31234