It is widely assumed that risk for most common medical disorders, especially for psychiatric disorders, involves interactions between multiple genes and between genes and the environment. Methods for testing and confirming epistasis in clinical samples, particularly the higher order interactions likely important in schizophrenia, are still being developed, and will mature as large scale datasets become available. Our Investigators have developed neuroimaging methods to confirm at a biological level clinical evidence of epistatic interactions within genes and between genes and have extended these findings to signaling within lymphoblast cell lines and in animal models involving breeding of genetically altered mouse strains. Our Clinical Study Section investigators continue to test specific hypotheses about gene-environment interactions, such as whether obstetrical complications related to hypoxic stress, long implicated as a risk factor for the development of adult schizophrenia, interact with genes involved in or affected by hypoxic-ischemic injury. Through the Clinical Brain Disorders Branch we have access to a large sample of probands, healthy siblings and healthy controls, which allows us to differentiate between state and potential trait clinical phenomena, it also permits an investigation of the genetics of protection within a family. In examining gene interactions, Ji et al. (Proceedings of the National Academy of Sciences, 2010) studied the role of the gene dysbindin (DTNBP1) in dopamine receptor trafficking and cortical gamma-aminobutyric acid (GABA) function. Genetic variants in DTNBP1 have been associated with schizophrenia. Patients have a reduced expression of dysbindin mRNA and protein in prefrontal cortex and hippocampus. It is unclear the role of dysbindin in the pathogenesis of schizophrenia or in neuron function in the circuitry underlying psychosis and related behaviors, but researchers are investigating its physiological role in neuronal function. They have found that downregulated dysbindin in cultured neurons leads to decreases in levels of Synaptosomal-associated protein 25 (SNAP-25) and extracellular glutamate or dopamine. Our research used dysbindin knockout mice, from the Sandy mouse line to study its role in dopamine signaling and neuronal function in the prefrontal cortex. There is reported evidence of increased dopamine D2 receptor but not D1 on neuronal cell surface in cortex. Our findings showed a disruption of dysbindin resulted in a marked decrease in the excitability of fast-spiking GABA interneurons in prefrontal cortex and striatum. The knockout mice also exhibited decreased inhibitory input to pyramidal neurons in layer V of the prefrontal cortex. The increased D2 signaling in the knockout mice fast-spiking interneurons was associated with increased neuronal firing in response to D2 agonist compared with the interneuron firing in wild-type mice neurons. We concluded that these results are evidence that dysbindin regulates prefrontal cortex function through D2-mediated modulation of GABA function. Another project of gene-gene interaction is presented in Nicodemus et al. (Human Genetic, 2010) who reported biological validation with functional neuroimaging of statistical epistasis between the genes DISC1, CIT (Citron Rho-interacting kinase) and NDEL1 (Nuclear distribution protein nudE-like 1). Disrupted-In-Schizophrenia 1 (DISC1) is a schizophrenia risk susceptibility gene that encodes a protein, which interacts with many other proteins, such as CIT and NDEL1. Many of its interacting proteins have been associated with psychosis. Epistasis between the genes was tested in a schizophrenia case-control study using Machine Learning Algorithms (MLAs). These analyses revealed a subset of 7 single nucleotide polymorphisms (SNPs) that underwent 2 SNP interaction modeling using ratio tests for nested unconditional logistic regression models. Of the 21 interactions, 7 were significant and of those 3 interactions were validated via fMRI study in healthy controls;risk associated alleles at both SNPs predicted prefrontal cortical inefficiency during a working memory task, a schizophrenia-linked intermediate biological phenotype. We failed to statistically replicate the interactions in other clinical samples. However, we did find that the CIT SNPs were located near the region that encodes the DISC1 interaction domain. Also, a DISC1 SNP acts as a splicing enhancer and the NDEL SNP is proximal to the encoding region of NDEL, which interacts with DISC1 proteins. Altogether, these results strongly suggest a biological basis for epistasis signals validated by fMRI. Studying the catechol-O-methyltransferase (COMT) gene in the context of other genes related to schizophrenia is a starting point to move beyond the cell surface in a neurotransmitter system critically important in cognition and psychosis. The work in this project has produced many insights for future projects related to cortical function in schizophrenia and DA influenced pathways. We are continuing to delve further into molecular and physiologic studies of the COMT mice. These studies are focused at: 1) identifying novel molecular targets in developing cortex dysregulated by genetic alteration in COMT and in further characterization of the effects on cortical microcircuit function;2) working in collaboration to cross breed COMT mice with AKT1 (encodes serine/threonine-specific protein kinase) heterozygote knockout mice, with the goal of identifying molecular targets of COMT-AKT1 interactions suggested by clinical work;and 3) exploring other epistasis models by cross breeding between COMT genetic mouse models with mice having perturbations in other potentially interacting genes, e.g. GAD1 (glutamate decarboxylase 1), GRM3 (metabotropic glutamate receptor 3), KCNH2 (potassium voltage-gated channel). These complex genetic alterations are expected to be more powerful in testing specific hypotheses about interactions between these genes and in uncovering novel pathways dysregulated by these interactions than in diverse clinical populations.
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| Tost, Heike; Weinberger, Daniel R (2011) RELN rs7341475 and schizophrenia risk: confusing, yet somehow intriguing. Biol Psychiatry 69:e19 |
| Papaleo, Francesco; Weinberger, Daniel R (2011) Dysbindin and Schizophrenia: it's dopamine and glutamate all over again. Biol Psychiatry 69:2-4 |
| Lemaitre, Herve; Mattay, Venkata S; Sambataro, Fabio et al. (2010) Genetic variation in FGF20 modulates hippocampal biology. J Neurosci 30:5992-7 |
| Zink, Caroline F; Stein, Jason L; Kempf, Lucas et al. (2010) Vasopressin modulates medial prefrontal cortex-amygdala circuitry during emotion processing in humans. J Neurosci 30:7017-22 |
| Tost, Heike; Alam, Tajvar; Meyer-Lindenberg, Andreas (2010) Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes. Neurosci Biobehav Rev 34:689-700 |
| Marenco, Stefano; Savostyanova, Antonina A; van der Veen, Jan Willem et al. (2010) Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT. Neuropsychopharmacology 35:1708-17 |
| Tost, Heike; Lipska, Barbara K; Vakkalanka, Radhakrishna et al. (2010) No effect of a common allelic variant in the reelin gene on intermediate phenotype measures of brain structure, brain function, and gene expression. Biol Psychiatry 68:105-7 |
| Bassett, Danielle S; Bullmore, Edward T; Meyer-Lindenberg, Andreas et al. (2009) Cognitive fitness of cost-efficient brain functional networks. Proc Natl Acad Sci U S A 106:11747-52 |
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