Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls

Kristin K Nicodemus, Amanda J Law, Eugenia Radulescu, Augustin Luna, Bhaskar Kolachana, Radhakrishna Vakkalanka, Dan Rujescu, Ina Giegling, Richard E. Straub, Kate McGee, Bert Gold, Michael Dean, Pierandrea Muglia, Joseph H Callicott, Hao-Yang Tan, Daniel R Weinberger

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)991-1001
Number of pages11
JournalArchives of General Psychiatry
Issue number10
Publication statusPublished - Oct 2010


  • Adaptor Proteins, Signal Transducing
  • Algorithms
  • Alleles
  • 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
  • Genotype
  • Humans
  • Image Processing, Computer-Assisted
  • Intracellular Signaling Peptides and Proteins
  • Logistic Models
  • Magnetic Resonance Imaging
  • Membrane Proteins
  • Memory, Short-Term
  • Neuregulin-1
  • Nitric Oxide Synthase Type I
  • Oxygen
  • Polymorphism, Single Nucleotide
  • Prefrontal Cortex
  • Proto-Oncogene Proteins c-akt
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-4
  • Reference Values
  • Schizophrenia
  • Journal Article
  • Research Support, N.I.H., Intramural


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