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Biological Validation of Increased Schizophrenia Risk With NRG1, ERBB4, and AKT1 Epistasis via Functional Neuroimaging in Healthy Controls

  1. Author:
    Nicodemus, K. K.
    Law, A. J.
    Radulescu, E.
    Luna, A.
    Kolachana, B.
    Vakkalanka, R.
    Rujescu, D.
    Giegling, I.
    Straub, R. E.
    McGee, K.
    Gold, B.
    Dean, M.
    Muglia, P.
    Callicott, J. H.
    Tan, H. Y.
    Weinberger, D. R.

  2. Author Address

    [Nicodemus, Kristin K.; Law, Amanda J.; Radulescu, Eugenia; Luna, Augustin; Kolachana, Bhaskar; Vakkalanka, Radhakrishna; Straub, Richard E.; Callicott, Joseph H.; Tan, Hao-Yang; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Nicodemus, Kristin K.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Nicodemus, Kristin K.] Univ Oxford, Dept Clin Pharmacol, Oxford, England. [Law, Amanda J.] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford, England. [Rujescu, Dan; Giegling, Ina] Univ Munich, Dept Psychiat, Sect Mol & Clin Neurobiol, D-8000 Munich, Germany. [McGee, Kate; Gold, Bert; Dean, Michael] NCI, Expt Immunol Lab, Frederick, MD 21701 USA. [Muglia, Pierandrea] GlaxoSmithKline Inc, Verona, Italy.;Weinberger, DR, NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH, Room 4S-235,10 Ctr Dr, Bethesda, MD 20892 USA.;weinberd@mail.nih.gov
    1. Year: 2010
    2. Date: Oct
  2. Journal: Archives of General Psychiatry
    1. 67
    2. 10
    3. Pages: 991-1001
  4. Type of Article: Article
  5. ISSN: 0003-990X
  1. Abstract:

    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 (:1 = 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 X 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. Arch Gen Psychiatry. 2010;67(10):991-1001

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External Sources

  1. View record in Web of Science®
  2. WOS: 000282917400002

Library Notes

  1. Fiscal Year: FY2010-2011
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