Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new

Porteous, David J.

doi:10.1016/j.gde.2008.07.005

Cited by 54 publications

(31 citation statements)

References 45 publications

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“…DISC1 regulates adult neurogenesis in mTOP-dependent manner and it inhibits AKT activity via DISC1-KIAA1212 binding (Porteous, 2008;). DISC1 has been also shown to have decreased level in kindling model (Fournier et al, 2010).…”

Section: Ectopic Neurogenesis and Mtor Pathwaymentioning

confidence: 99%

Frontier of Epilepsy Research - mTOR signaling pathway

Cho

2011

Exp Mol Med

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Section: Ectopic Neurogenesis and Mtor Pathwaymentioning

confidence: 99%

Frontier of Epilepsy Research - mTOR signaling pathway

Cho

2011

Exp Mol Med

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“…However, negative results have been also reported. 8 Increasing evidence suggests that bipolar disorder and schizophrenia could share many risk genes, [12][13][14] although evidence for cadherins is still limited. 4 Note, however, that the role of FAT in neuronal migration and positioning during development makes it a good candidate gene for schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

No influence of FAT polymorphisms in response to aripiprazole

et al. 2009

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The aim of this study was to investigate possible influences of a set of markers in the FAT gene (rs2306987, rs2306990, rs2637777 and rs2304865) on efficacy and tolerability of aripiprazole in the treatment of schizophrenic patients. Efficacy was assessed at baseline and weeks 1, 2, 4, 6, 8 and 12 using the Clinical Global Impression Severity and Improvement scale (CGI-S; CGI-I), the Brief Psychiatric Rating Scale and the Schedule for the Assessment of Negative Symptoms scale. Side effects were evaluated by means of the Simpson-Angus Scale for Extrapyramidal Symptoms, the Barnes Akathisia Scale and the Abnormal Involuntary Movement Scale. Multivariate analyses were employed to test possible influences of single nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. No relevant association between FAT variants and clinical or safety scores was observed. Haplotype analysis did not reveal any significant association with clinical and safety scores at any time as well. Our data suggest no association between investigated alleles and genotypes in FAT and response to aripiprazole. However, because several limitations characterize the present study, further investigations on larger studies are required.

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“…If a conservative 2 % of cases can be explained by highly penetrant mutations in this single gene, and this case is not exceptional, then single mutations could clearly numerically account for all cases of SZ. Importantly, many of the implicated genes have biologically plausible roles in neural development (Guilmatre et al 2009 ;Raychaudhuri et al 2009 ;Sebat et al 2009), and when mutated in mice model aspects of SZ with good construct, face and predictive validity (Waddington et al 2007 ;Carpenter & Koenig, 2008 ;Porteous, 2008). Average penetrance of 50 % is assumed, based on monozygotic (MZ) twin concordance.…”

Section: Empirical Support For the Rare Variants Modelmentioning

confidence: 99%

Rethinking the Genetic Architecture of Schizophrenia

Mitchell¹,

Porteous²

2010

Schizophrenia Research

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Background. For many years, the prevailing paradigm has stated that in each individual with schizophrenia (SZ) the genetic risk is due to a combination of many genetic variants, individually of small effect. Recent empirical data are prompting a re-evaluation of this polygenic, common disease-common variant (CDCV) model. Evidence includes a lack of the expected strong positive findings from genome-wide association studies and the concurrent discovery of many different mutations that individually strongly predispose to SZ and other psychiatric disorders. This has led some to adopt a mixed model wherein some cases are caused by polygenic mechanisms and some by single mutations. This model runs counter to a substantial body of theoretical literature that had supposedly conclusively rejected Mendelian inheritance with genetic heterogeneity. Here we ask how this discrepancy between theory and data arose and propose a rationalization of the recent evidence base.Method. In light of recent empirical findings, we reconsider the methods and conclusions of early theoretical analyses and the explicit assumptions underlying them.Results. We show that many of these assumptions can now be seen to be false and that the model of genetic heterogeneity is consistent with observed familial recurrence risks, endophenotype studies and other populationwide parameters.Conclusions. We argue for a more biologically consilient mixed model that involves interactions between diseasecausing and disease-modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms.

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Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new

Cited by 54 publications

References 45 publications

Frontier of Epilepsy Research - mTOR signaling pathway

Frontier of Epilepsy Research - mTOR signaling pathway

No influence of FAT polymorphisms in response to aripiprazole

Rethinking the Genetic Architecture of Schizophrenia

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