An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes

Prog Neuropsychopharmacol Biol Psychiatry. 2010 Oct 1;34(7):1259-65. doi: 10.1016/j.pnpbp.2010.07.001. Epub 2010 Jul 16.


Background: Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls.

Methods: Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records.

Results: Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume.

Conclusions: The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples.

MeSH terms

  • Adult
  • Brain-Derived Neurotrophic Factor / genetics
  • Carrier Proteins / genetics
  • Case-Control Studies
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Female
  • Genotype
  • Hippocampus / pathology*
  • Humans
  • Hypoxia / genetics*
  • Image Processing, Computer-Assisted / methods
  • Magnetic Resonance Imaging / methods
  • Male
  • Middle Aged
  • Neuregulin-1 / genetics
  • Obstetric Labor Complications / genetics*
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Receptors, Metabotropic Glutamate / genetics
  • Schizophrenia / genetics*
  • Schizophrenia / pathology*
  • Young Adult


  • Brain-Derived Neurotrophic Factor
  • Carrier Proteins
  • DTNBP1 protein, human
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Neuregulin-1
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 3