期刊
ARCHIVES OF GENERAL PSYCHIATRY
卷 67, 期 10, 页码 991-1001出版社
AMER MEDICAL ASSOC
DOI: 10.1001/archgenpsychiatry.2010.117
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资金
- GlaxoSmithKline
- National Institute of Mental Health
- MRC [G120/997] Funding Source: UKRI
- Medical Research Council [G120/997] Funding Source: researchfish
- NATIONAL INSTITUTE OF MENTAL HEALTH [R03MH096539] Funding Source: NIH RePORTER
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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