Abstract
Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p < 0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder.
Keywords: G72, DAAO, glutamate, schizophrenia, bipolar disorder, functional magnetic resonance imaging, vulnerability, genotypes, psychosis, prodromal symptoms
Current Pharmaceutical Design
Title: Genetic Vulnerability to Psychosis and Cortical Function: Epistatic Effects between DAAO and G72
Volume: 18 Issue: 4
Author(s): Mechelli Andrea, Fusar-Poli Paolo, Prata Diana, Papagni Sergio Alessandro, Tognin Stefania, Kambeitz Joseph, Fu Cynthia, Picchioni Marco, Walshe Muriel, Toulopoulou Timothea, Bramon Elvira, Murray Robin and McGuire Philip
Affiliation:
Keywords: G72, DAAO, glutamate, schizophrenia, bipolar disorder, functional magnetic resonance imaging, vulnerability, genotypes, psychosis, prodromal symptoms
Abstract: Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p < 0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder.
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Andrea Mechelli, Paolo Fusar-Poli, Diana Prata, Sergio Alessandro Papagni, Stefania Tognin, Joseph Kambeitz, Cynthia Fu, Marco Picchioni, Muriel Walshe, Timothea Toulopoulou, Elvira Bramon, Robin Murray and Philip McGuire, Genetic Vulnerability to Psychosis and Cortical Function: Epistatic Effects between DAAO and G72, Current Pharmaceutical Design 2012; 18 (4) . https://dx.doi.org/10.2174/138161212799316037
DOI https://dx.doi.org/10.2174/138161212799316037 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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