CONTEXT: NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis.
OBJECTIVE: To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP.
DESIGN: Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls.
PARTICIPANTS: A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172).
MAIN OUTCOME MEASURES: Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging.
RESULTS: We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling.
CONCLUSION: Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.
|Number of pages||11|
|Journal||Archives of General Psychiatry|
|Publication status||Published - Oct 2010|
- Adaptor Proteins, Signal Transducing
- Artificial Intelligence
- Case-Control Studies
- Disks Large Homolog 4 Protein
- Epistasis, Genetic
- Genetic Carrier Screening
- Genetic Markers
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Image Processing, Computer-Assisted
- Intracellular Signaling Peptides and Proteins
- Logistic Models
- Magnetic Resonance Imaging
- Membrane Proteins
- Memory, Short-Term
- Nitric Oxide Synthase Type I
- Polymorphism, Single Nucleotide
- Prefrontal Cortex
- Proto-Oncogene Proteins c-akt
- Receptor, Epidermal Growth Factor
- Receptor, ErbB-4
- Reference Values
- Journal Article
- Research Support, N.I.H., Intramural