Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland

McGinnis, Ralph; Fox, Helen; Yates, Phillip A.; Cameron, L.A.; Barnes, Michael R.; Gray, Ian C.; Spurr, Nigel K.; Hurko, Orest; Clair, David St

doi:10.1038/88839

Cited by 57 publications

(44 citation statements)

References 4 publications

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“…91 However, replication attempts have been largely negative. [92][93][94][95][96] A potential role of the tumour necrosis factor alpha (TNFa) gene for susceptibility to schizophrenia has been proposed by Bouin et al, 97 who reported a positive association between a biallelic base exchange polymorphism that directly affects TNFa plasma levels and schizophrenia. TNFa, produced by glial cells, influences synaptic plasticity and modulates responses to neural injury.…”

Section: Discussionmentioning

confidence: 99%

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

et al. 2003

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As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/ DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic firstdegree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS43.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.

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Section: Discussionmentioning

confidence: 99%

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

et al. 2003

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“…However, Sklar et al [2001] found no significant association between NOTCH4 and schizophrenia. McGinnis et al [2001] also showed no significant association between NOTCH4 and schizophrenia.We also performed a family-based association study of NOTCH4 and schizophrenia [Takahashi et al, 2003a]. In this study using Sanger sequencing, we sequenced genomic DNA around rs387071 that was a significant SNP in the original study [Wei and Hemmings, 2000].…”

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confidence: 90%

Heterogeneity of schizophrenia: Genetic and symptomatic factors

Takahashi

2013

American J of Med Genetics Pt B

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Schizophrenia may have etiological heterogeneity, and may reflect common symptomatology caused by many genetic and environmental factors. In this review, we show the potential existence of heterogeneity in schizophrenia based on the results of our previous studies. In our study of the NOTCH4 gene, there were no significant associations between any single nucleotide polymorphisms (SNPs) of NOTCH4 and schizophrenia. However, exploratory analyses suggested that the SNP, rs3134928 may be associated with early-onset schizophrenia, and that rs387071 may be associated with schizophrenia characterized by negative symptoms. In our highly familial schizophrenia study, the African-American cohort without environmental exposure showed a possible linkage at marker 8p23.1 in the dominant model and in the European-American cohort, a marker at 22q13.32 showed a probable linkage in the recessive model. In the less familial schizophrenia families, these linkages were not shown. Based on our eye movement study, a putative subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization may be associated with chromosome 22q11. We consider that a sample stratification approach may clarify the heterogeneity of schizophrenia. Therefore, this approach may lead to a more straightforward way of identifying susceptibility genes of schizophrenia. Ó 2013 Wiley Periodicals, Inc.Key words: schizophrenia; heterogeneity; copy number variant; sample stratification approach INTRODUCTIONSchizophrenia is a severe psychiatric illness with a prevalence of approximately 1%. Epidemiological studies of schizophrenia have shown that genetic components play an important role in the development of schizophrenia [Tsuang and Faraone, 1995;Tsuang, 2000]. Its heritability was estimated to be $80% [Sullivan et al., 2003]. However, the genetic etiology of schizophrenia is still unclear. One of the most important sources of conflict may be the potential etiological heterogeneity of schizophrenia. Many investigators have suggested that schizophrenia is not a single disease entity, but may reflect common symptomatology caused by many genetic and environmental factors [Tsuang et al., 1990;Tsuang and Faraone, 1995;Tsuang, 2000;Sawa and Snyder, 2002;Takahashi et al., 2005]. Since human diseases have a noticeable genetic heterogeneity [McClellan and King, 2010], when studying the genetic etiology of schizophrenia, heterogeneity should be part of the study design [Sebat et al., 2009].Recent copy member variant (CNV) studies also indicate the heterogeneity of schizophrenia. Based on the findings of CNV studies, an understanding of the genetic heterogeneity of complex disorders, such as schizophrenia and autism, has begun [Bassett et al., 2010]. Because results have shown a rare mutation with a large CNV effect and a common mutation with small/modest effect by single nucleotide polymorphism (SNP), schizophrenia may be characterized by much more genetic heterogeneity than was formerly thought [Sebat et al., 2009]. A micro...

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“…The schizophrenic and control groups have been described previously. 28,29 All bipolar disorders diagnosed by case note examination, clinical interview, and OPCRIT met the DSM 1 V criteria for primary diagnosis. The mean age of the sample is 34710 years, and the mean age of onset is 1977.3 years.…”

Section: Methodsmentioning

confidence: 99%

BDNF gene is a risk factor for schizophrenia in a Scottish population

et al. 2005

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Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P ¼ 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/ met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (Po1 Â 10 À8 ) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried.

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Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland

Cited by 57 publications

References 4 publications

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

Heterogeneity of schizophrenia: Genetic and symptomatic factors

BDNF gene is a risk factor for schizophrenia in a Scottish population

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