title: Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.
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, P(nominal)  = 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, P(nominal)  = 0.0001 and rs1806205, P(nominal)  = 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.
authors.affiliation: Department of Human Genetics, Aarhus University, Aarhus, Denmark. ditte@humgen.au.dk
authors.forename: Ditte
authors.initials: D
authors.lastname: Demontis
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.forename: Henriette N
authors.initials: HN
authors.lastname: Buttenschøn
authors.forename: Anne
authors.initials: A
authors.lastname: Hedemand
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Pedersen
authors.forename: Jakob
authors.initials: J
authors.lastname: Grove
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Flint
authors.forename: Merete
authors.initials: M
authors.lastname: Nordentoft
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: David M
authors.initials: DM
authors.lastname: Hougaard
authors.forename: Karina M
authors.initials: KM
authors.lastname: Sørensen
authors.forename: Robert H
authors.initials: RH
authors.lastname: Yolken
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.forename: Preben Bo
authors.initials: PB
authors.lastname: Mortensen
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006561:Herpes Simplex; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C485668:GRIN1 protein, human; C121001:NR2B NMDA receptor