Heterogeneity of schizophrenia: Genetic and symptomatic factors

Abstract

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...

Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

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