Analysis of 94 Candidate Genes and 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia

Harvard University, Cambridge, Massachusetts, United States
American Journal of Psychiatry (Impact Factor: 12.3). 04/2011; 168(9):930-46. DOI: 10.1176/appi.ajp.2011.10050723
Source: PubMed


The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia.
Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects.
Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.
This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."

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Available from: Tiffany A Greenwood, Oct 26, 2015
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    • "Importantly, human SP4 gene was found to be deleted in schizophrenia (International Schizophrenia Consortium, 2008) 20,21, and its expression was decreased in the postmortem brains of bipolar patients [22]. Moreover, human SP4 gene single nucleotide polymorphisms (SNPs) were also reported to associate with bipolar disorder, schizophrenia, and major depression [23]–[26]. Together, these data demonstrated Sp4 hypomorphic mice as a promising hypoglutamatergic model for schizophrenia. In the present work, we report that Sp4 hypomorphic mice also exhibit prolonged responses to NMDAR antagonists germane to Luby’s striking findings in schizophrenia more than 50 years ago. "
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    ABSTRACT: It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.
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    • "Schizophrenia is a severe mental illness that represents the fifth most important cause of years lost due to disability worldwide [WHO 2004]. Its inheritance appears in line with other complex genetic diseases, where the phenotype expresses the combined influence and interaction of multiple genes [Stefansson et al., 2009; Greenwood et al., 2011; Ayalew et al., 2012]. However, the substantial variation in the clinical presentation of patients with schizophrenia introduces important limitations to unravel the underlying causes of this disorder. "
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    • "Here, we will summarize recent findings on some of the most prominent ones and explore their roles in spine dynamics. A large number of genetic linkage and association studies have suggested that the Neuregulin 1 (NRG1) and ERBB4 genes may be risk factors for schizophrenia (Stefansson et al. 2002; Hall et al. 2006; Munafo et al. 2006, 2008; Silberberg et al. 2006; Law et al. 2007; Nicodemus et al. 2010; Tan et al. 2010) and its endophenotypes (Greenwood et al. 2011, 2012). These genes also regulate several biological processes altered in schizophrenia (Buonanno and Fischbach 2001; Mei and Xiong 2008; Buonanno 2010). "
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