Family-based association study of the NOTCH4 gene in schizophrenia using Japanese and Chinese samples

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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...

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Heterogeneity of schizophrenia: Genetic and symptomatic factors

Takahashi

2013

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“…They found that the age of onset in males was highly associated with the SNP2-T allele (P < 0.0001) although such an association was not shown in females (P ¼ 0.502). In a family-based study using Japanese and Chinese samples, Takahashi et al [2003] found that the SNP_A marker was associated with early-onset schizophrenia (P ¼ 0.0076) and that the SNP1 marker was associated with the illness characterized with numerous negative symptoms (P ¼ 0.0045).…”

Section: Discussionmentioning

confidence: 99%

“…In an initial study, the NOTCH4 locus was found to be associated with schizophrenia in a British population [Wei and Hemmings, 2000]. This finding appears to be supported by several independent studies [Cichon et al, 2001;Klempan et al, 2001;Anttila et al, 2003Anttila et al, , 2004Skol et al, 2003;Takahashi et al, 2003;Luo et al, 2004;Prasad et al, 2004;Wang et al, 2005] although some others have failed to replicate it [Imai et al, 2001;McGinnis et al, 2001;Sklar et al, 2001;Ujike et al, 2001;Fan et al, 2002;Carmine et al, 2003;Kaneko et al, 2004;Tochigi et al, 2004]. The replication work was designed to apply either a population-based study or a family-based study, or both, among different populations.…”

Section: Introductionmentioning

confidence: 87%

“…Several additional DNA markers in and around the NOTCH4 locus have been investigated in schizophrenia by some other studies. These markers include the (GAAG)n repeats in the 5 0 -flanking region of the gene [Prasad et al, 2004], SNP_A, _B, _C, and, _D markers around SNP1 [Takahashi et al, 2003], as well as rs2071284, rs520688, rs520692, rs915894, and rs422951 [Tochigi et al, 2004;Zhang et al, 2004]. Of these additional markers, Prasad et al [2004] found that the (GAAG) 50 allele showed preferential transmission in Indian and USA family trios (Table I); Takahashi et al [2003] found that the SNP_A marker was associated with early-onset schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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A review and re‐evaluation of an association between the NOTCH4 locus and schizophrenia

Wang

Wei²,

Zhang

et al. 2006

This work reviewed all the reports on the NOTCH4 gene in schizophrenia, which have been published since the gene was found to be associated with illness among a British population in 2000. The results from independent studies were inconsistent. Allelic heterogeneity, clinical diagnosis, ethnical backgrounds, and linkage disequilibrium (LD) structures in the human genome may be major reasons for poor replication. A couple of studies suggested that the NOTCH4 gene could play a role in a subgroup of the disease, such as early-onset schizophrenia and negative symptoms. A single study revealed a weak association of the NOTCH4 gene with frontal lobe brain volumes and a strong association with frontal lobe cognitive performance. A meta-analysis showed stronger evidence of the NOTCH4 association in family-based studies than in case-control studies. In a previous study, we found that rs520692, a single nucleotide polymorphism (SNP) at the NOTCH4 locus, was associated with schizophrenia in a Chinese population. In the present study, we applied a large sample size to re-evaluate our initial findings and then confirmed the rs520692 association with illness. The pairwise measures did not show strong LD between paired SNPs although the SNPs tested are located within a 34-kb region, suggesting that LD within the NOTCH4 gene has been broken rapidly by historical recombination in the Chinese population. Taken together, the NOTCH4 gene may be associated with schizophrenia but how the gene contributes to the etiology of the illness needs a further investigation.

Association of six polymorphisms of the NOTCH4 gene with schizophrenia in the Japanese population

Tochigi

Zhang

Umekage

et al. 2004

The NOTCH4 gene is located at 6p21.3 and involved in the development and patterning of the central nervous systems. Recently, Wei and Hemmings [2000] observed that the gene was associated with schizophrenia. Subsequent to the report, several studies investigated the gene in schizophrenia, with controversial and inconclusive results. In the present study, we investigated six polymorphisms (SNPs 1-5 and a CTG repeat) of the gene in Japanese subjects with schizophrenia (n = 284) and the same number of controls. The polymorphisms include SNP5, which has been observed to be associated with schizophrenia in a Chinese population and two new SNPs 3-4 adjacent to SNP5, in addition to the SNPs 1-2 and the CTG repeat, which were suggested for the association with the disease in the previous study. As a result, no significant difference in genotypic distributions or allelic frequencies of the six polymorphisms of the gene was observed between the patients and the controls. Also, no significant difference was found in frequencies of haplotypes of the six polymorphisms between the patients and the controls. However, the distribution of SNP2 was significantly deviated from Hardy-Weinberg equilibrium in the patients (P = 0.000986), not in the controls, which could be a chance or due to an association of SNP2 with the disease. In conclusion, the present study provided no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population.