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: 13.56). 04/2011; 168(9):930-46. DOI: 10.1176/appi.ajp.2011.10050723
Source: PubMed

ABSTRACT 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 17, 2014
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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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    • "Cette approche pose cependant un problème méthodologique : elle ne peut se baser sur la recherche des SNP les plus signifi cativement associés à la variation d'un trait ou d'un endophénotype. Elle doit bénéfi cier soit d'une approche prenant en compte des gènes connus et des réseaux préalablement défi nis [24], mais qui peuvent laisser dans l'ombre les réseaux les plus décisifs s'ils sont inconnus, soit d'une approche qui se décale du génome au transcriptome, qui, en rendant compte à un moment donné de l'expression du génome, est plus en phase avec la fonctionnalité des réseaux moléculaires. On n'est pas étonné de constater, en miroir de la diffi culté de mettre en évidence des gènes ayant un effet majeur dans la vulnérabilité à la dépression, que les recherches de ce type aient permis de mettre en évidence que les gènes les plus signifi cativement dérégulés chez les patients déprimés soient à la périphérie des réseaux moléculaires, loin des hubs des fonctions biologiques fondamentales du cerveau [25]. "
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