ArticleArchives of general psychiatry2010
Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls.
Article in Archives of general psychiatry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 122 citations in OpenAlex.
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- A primer on the use of machine learning to distil knowledge from data in biological psychiatry.Molecular psychiatry · 2024Review
- Chronic methamphetamine interacts with BDNF Val66Met to remodel psychosis pathways in the mesocorticolimbic proteome.Molecular psychiatry · 2021Article
- Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation.Cell death & disease · 2021Article
- Translational genomics and beyond in bipolar disorder.Molecular psychiatry · 2021Review
- Article
- Ketamine Affects the Expression of ErbB4 in the Hippocampus and Prefrontal Cortex of Rats.Journal of molecular neuroscience : MN · 2020Article
- Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development.Schizophrenia research · 2020Article
- Transcriptome analysis of fibroblasts from schizophrenia patients reveals differential expression of schizophrenia-related genes.Scientific reports · 2020Article
- Nrg1 Intracellular Signaling Is Neuroprotective upon Stroke.Oxidative medicine and cellular longevity · 2019Article
- Pleiotropic action of genetic variation in ZNF804A on brain structure: a meta-analysis of magnetic resonance imaging studies.Neuropsychiatric disease and treatment · 2019Article
- Review
- Increased circulating regulatory T cells in medicated people with schizophrenia.Psychiatry research · 2018Article
- Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder.Psychiatric genetics · 2018Article
- Effects of Schizophrenia Polygenic Risk Scores on Brain Activity and Performance During Working Memory Subprocesses in Healthy Young Adults.Schizophrenia bulletin · 2018Article
- BACE1-Deficient Mice Exhibit Alterations in Immune System Pathways.Molecular neurobiology · 2018Article
- Neuroimaging genomics in psychiatry-a translational approach.Genome medicine · 2017Review
- Genome-wide association study of working memory brain activation.International journal of psychophysiology : official journal of the International Organization of Psychophysiology · 2017Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 4 countries.
Funding
Abstract
contextNRG1 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.
objectiveTo examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP.
designSchizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls.
participantsA 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 measuresEpistatic 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.
resultsWe 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.
conclusionOur data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.
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