Schizophrenia is a psychosis, a disorder of thought and sense of self. Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and ... Schizophrenia is a psychosis, a disorder of thought and sense of self. Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. There is no characteristic pathology, such as neurofibrillary tangles in Alzheimer disease (104300). Schizophrenia is a common disorder with a lifetime prevalence of approximately 1%. It is highly heritable but the genetics are complex. This may not be a single entity. - Reviews In a review of schizophrenia, van Os and Kapur (2009) noted that in Japan the term schizophrenia was abandoned and the illness is now called integration-dysregulation syndrome.
Schizophrenia often develops in young adults who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, disordered thinking and concentration, erratic behavior, ... Schizophrenia often develops in young adults who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, disordered thinking and concentration, erratic behavior, as well as social and occupational deterioration (Andreasen, 1995). In his first description of dementia praecox, Kraepelin identified subtypes of schizophrenia: hebephrenic, catatonic, and paranoid (Diefendorf, 1902). The utility and validity of these subtypes was long a subject of debate. Kendler et al. (1994) sought to clarify differences in outcome and familial psychopathology among these 3 subtypes in the Roscommon Family Study of severe mental illness conducted in a rural county in western Ireland. They found that the subtypes did not 'breed true' within families. They concluded that from a familial perspective the subtypes are not etiologically distinct syndromes. Kendler and Hays (1982) compared a group of 30 patients with familial schizophrenia (defined as having an affected first-degree relative) and a group of 83 cases of sporadic schizophrenia. No difference in the intensity of (1) flattened, depressed, or elevated affect, (2) auditory hallucinations, or (3) delusions was found; however, more of the familial (56.7%) than of the sporadic (18.1%) schizophrenic patients had severe thought disorders. EEGs performed while the patients were taking neuroleptics showed abnormality in 72.3% of sporadic cases and 43.3% of familial cases. Extrapyramidal signs such as bradykinesia, rigidity, or dyskinesias in patients with schizophrenia are usually attributed to antipsychotic drugs, many of which are dopamine-receptor antagonists. Chatterjee et al. (1995) prospectively studied 89 patients presenting with a first episode of schizophrenia who had never taken neuroleptic medications. Using the Simpson Dyskinesia Rating Scale, they found 16.9% (15) of these individuals to have significant extrapyramidal dysfunction on presentation. Twelve of the patients had akinesia, 6 had rigidity, 1 had cogwheeling, and 1 had mild spontaneous dyskinesia. These observations gave support to earlier proposals that the basal ganglia may be involved in the pathophysiology of schizophrenia. Kunugi et al. (1994) found no significant difference in head circumference at birth between 64 infants who later developed schizophrenia and 45 of their healthy sibs. Nopoulos et al. (1995) demonstrated decreased volume of the frontal lobe and increased volume of the intersulcal CSF in 12 males and 12 females presenting with a first episode of schizophrenia, compared to 24 controls matched for age, height, weight, parental social class, and paternal and maternal education. Eye movement disturbances have been found in about 40 to 80% of patients with schizophrenia, about 25 to 40% of their healthy first-degree relatives, and in less than 10% of healthy control subjects (Holzman, 2000). Schizophrenia and bipolar disorder (125480) are generally considered to be separate entities, but patients who exhibit multiple symptoms of both disorders are often given the hybrid diagnosis schizoaffective disorder (Blacker and Tsuang, 1992). The clinical features of such patients supported the argument that schizophrenia and bipolar disorder are variant expressions of a diathesis, in part because of the similar disease frequencies, ages at onset, and absence of sex bias in the 2 disorders. Hallmayer et al. (2005) pointed out that Kraepelin (1909) viewed the disorder he termed dementia praecox as a cognitive disorder. Coining the term schizophrenia to replace dementia praecox, Bleuler (1920) emphasized that it 'is not a disease in the strict sense, but appears to be a group of diseases...Therefore we should speak of schizophrenias in the plural.' Hallmayer et al. (2005) stated that the inherent heterogeneity originally recognized has been obfuscated in modern diagnostic classifications, which are designed to meet the needs of patient management, not fundamental research, and which may not target phenotypes anchored in the biology of the illness. Limited understanding of phenotypic heterogeneity is a common challenge in genetic studies of complex disorders.
Using data from a regularly updated online database of all published genetic association studies for schizophrenia (SzGene), Allen et al. (2008) carried out random-effects metaanalyses for all polymorphisms having genotype data available in at least 4 independent case-control ... Using data from a regularly updated online database of all published genetic association studies for schizophrenia (SzGene), Allen et al. (2008) carried out random-effects metaanalyses for all polymorphisms having genotype data available in at least 4 independent case-control samples. Across 118 metaanalyses, a total of 24 genetic variants in 16 different genes showed nominally significant effects with average summary odds ratios of approximately 1.23: APOE (107741), COMT (116790), DRD2 (126450), DRD4 (126452), GRIN2B (138252), IL1B (147720), MTHFR (607093), SLC6A4 (182138), TPH1 (191060), DAO (124050), DRD1 (126449), DTNBP1 (607145), GABRB2 (600232), HP (140100), PLXNA2 (601054), and TP53 (191170). The last 7 of these had not previously been metaanalyzed. According to proposed criteria for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), associations with variants in 4 of these genes, DRD1, DTNBP1, MTHFR, and TPH1, were characterized as showing 'strong' epidemiologic credibility. Allen et al. (2008) concluded that the SzGene database represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. They noted that in their study 94, or 80%, of the SNPs in 45 genes showed no significant association with schizophrenia after all published case-control samples were metaanalyzed, either in the analyses combining all samples of all ancestries or across samples of European-only ancestry. Sebat et al. (2009) reported on the role of rare structural variants in schizophrenia and discussed the implications for psychiatric research. Xu et al. (2012) sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases from Afrikaner and U.S. cohorts, as well as 34 unaffected trios, and observed in cases an excess of de novo nonsynonymous single-nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations relative to controls. Xu et al. (2012) found 4 genes, LAMA2 (156225), DPYD (612779), TRRAP (603015), and VPS39 (612188), affected by recurrent de novo events within or across the 2 populations, which is unlikely to have occurred by chance. Xu et al. (2012) showed that de novo mutations affect genes with diverse functions and developmental profiles, but they also found a substantial contribution of mutations in genes with higher expression in early fetal life. - Association with the MTHFR Gene on Chromosome 1p36 Lewis et al. (2005) conducted a metaanalysis of 6 studies (1,119 cases, 1,308 controls) involving the 677C-T polymorphism (607093.0003) in the methylenetetrahydrofolate reductase gene (MTHFR: 607093) on chromosome 1p36 and schizophrenia risk. They found that TT homozygotes had a significantly increased risk (odds ratio, 1.48; 95% CI, 1.18-1.86), supporting the role of this gene and folate metabolism as schizophrenia risk factors. Muntjewerff et al. (2005) conducted a case-control study to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations and the 677TT MTHFR haplotype in 254 patients with schizophrenia and 414 healthy controls of Dutch ancestry. Homocysteine concentrations were stratified into quartiles, revealing that the risk of schizophrenia increased in the fourth and third quartile versus the lowest quartile (OR, 3.3, 95% CI, 1.2-9.2 and OR, 3.1, 95% CI, 1.2-8.0, respectively). A significant dose-response relationship of increasing homocysteine levels and increasing risk of schizophrenia was observed (p = 0.036). The 677TT genotype was associated with an odds ratio of 1.6 (95% CI, 0.96-2.8) of having schizophrenia. Heterozygosity for the T allele compared to homozygosity for the C allele accounted for an odds ratio of 1.3 (95% CI, 0.91-1.8). Elevated homocysteine levels and the TT genotype were associated with increased risk of schizophrenia. See 607093.0003 for additional information regarding disturbed homocysteine metabolism, the 677TT MTHFR genotype, and the risk of schizophrenia. - Association with the NOS1AP Gene on Chromosome 1q23 Brzustowicz et al. (2000) performed a genomewide scan for schizophrenia susceptibility loci in 22 extended Canadian families with high rates of schizophrenia, which provided highly significant evidence of linkage to chromosome 1q21-q22, with a maximum lod score of 6.5. Brzustowicz et al. (2000) concluded that their results should provide sufficient power to allow the positional cloning of the underlying susceptibility gene. The disorder in the families studied by Brzustowicz et al. (2000) segregated in a unilineal autosomal dominant manner. An average of 13.8 individuals per family participated in the study, and 5 families had 20 to 29 members participating. An average of 3.6 individuals with schizophrenia or schizoaffective disorder participated per family, with 15 individuals with these diagnoses participating in the largest family. To minimize multiple tests, Brzustowicz et al. (2000) selected 4 genetic models, dominant and recessive for each of a 'narrow' and a 'broad' diagnostic classification. The narrow classification included the diagnoses of schizophrenia and chronic schizoaffective disorder; the broad classification included these and several schizophrenia-spectrum disorders. Brzustowicz et al. (2000) performed simulation studies with 2,500 unlinked replicates to determine the lod scores corresponding to P = 0.05. This produced a lod score threshold for significance of 3.3 under the hypothesis of homogeneity and 3.5 under the hypothesis of heterogeneity. The highest lod score obtained was 5.79 with P less than 0.0002 under the narrow definition of illness with a recessive mode of inheritance with marker D1S1679, which maps to chromosome 1q22. Lod scores of greater than 2.0 were obtained with 5 adjacent markers from 1q, spanning a region of approximately 39 cM. Significant linkage was not detected to any other chromosome when 2-point analysis was used. Multipoint analysis with chromosome 1 markers produced the maximum lod score of 6.50 (p less than 0.0002) between the markers D1S1653 and D1S1679 under the recessive-narrow model, with an estimated 75% of families linked to this locus. Levinson et al. (2002) evaluated the evidence for genetic linkage of schizophrenia to chromosome 1q by genotyping 16 DNA markers across 107 cM of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the 8 individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. Levinson et al. (2002) concluded that if schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small. Macgregor et al. (2002) suggested that locus heterogeneity adequately explains the failure of an affected sib pair analysis with any reasonable sample size to replicate results from large extended families, and they had strong reservations about the limited interpretation of the results in the study by Levinson et al. (2002). Bassett et al. (2002) also suggested that the failure of Levinson et al. (2002) to detect linkage to 1q suggested a failure of their study design for that locus. Levinson et al. (2002) replied that the significant findings by Brzustowicz et al. (2000), Gurling et al. (2001), Blackwood et al. (2001), and Ekelund et al. (2001) suggested that there probably is linkage to chromosome 1q. In an erratum to their reply, Levinson et al. (2002) stated that they had made an error in their analysis of the data of Brzustowicz et al. (2000). The correction indicated that linkage to schizophrenia on proximal 1q in the Canadian sample of Brzustowicz et al. (2000) was in fact highly significant. Brzustowicz et al. (2002) conducted fine mapping of the schizophrenia susceptibility locus on chromosome 1, which they referred to as the 1q22 locus, in the same set of individuals studied by Brzustowicz et al. (2000). A maximum multipoint lod score of 6.50 was found for an interval of less than 3 cM, corresponding to approximately 1 Mb. Physical mapping and sequence analysis from this region confirmed the presence of a tandem duplication of approximately 81 kb, containing heat shock protein genes and low-affinity IgG receptor genes, including FCGR2A (146790). The sequences of the 2 copies of this duplication were approximately 97% identical, which had led to the collapse of the 2 copies into 1 in the human genome sequence draft. Brzustowicz et al. (2002) suggested that this duplication may be involved in genomic instability, leading to gene deletion, and therefore presented an intriguing candidate locus for schizophrenia susceptibility. In the same set of Canadian families studied by Brzustowicz et al. (2000, 2002), Brzustowicz et al. (2004) examined the 5.4-kb region of strongest linkage and found that all markers exhibiting significant linkage disequilibrium were located within the NOS1AP (CAPON) gene. In further studies on these families, Wratten et al. (2009) tested 30 SNPs exhibiting strong evidence of LD for regulatory function by luciferase reporter assay. One of 3 SNPs that produced posterior probability of linkage disequilibrium (PPLD) values greater than 40%, dbSNP rs12742393, demonstrated significant allelic expression differences in 2 human neural cell lines. Allelic variation at this SNP was shown to alter the affinity of nuclear protein binding to this region of DNA. Wratten et al. (2009) suggested that the A allele of dbSNP rs12742393 is a risk allele associated with schizophrenia that acts by enhancing transcription factor binding and increasing gene expression. Zheng et al. (2005) examined 9 SNPs in an approximately 236-kb region of the NOS1AP gene in 664 unrelated schizophrenia patients and 941 controls in the Chinese Han population. They detected a significant difference in allele distributions of dbSNP rs348624 (which was in complete LD with dbSNP rs1964052) (p = 0.000017; p = 0.000153 after Bonferroni correction). The frequency of a C rather than a T allele was greater in patients (87.3%) than in controls (81.6%). Kremeyer et al. (2009) genotyped 24 SNPs across 314 kb of the NOS1AP gene in a schizophrenia trio sample (102 patients) in a South American isolate (Antioquia). Eight SNPs showed significant association to schizophrenia (p = 0.004); 7 were in high LD with each other and were located in intron 2 of the gene. Two of them, the T allele of dbSNP rs1415263 and the C allele of dbSNP rs4145621, had also been found to show significant association by Brzustowicz et al. (2004). Kremeyer et al. (2009) noted that Xu et al. (2005) had found the overexpression of the short NOS1AP isoform in the schizophrenic brain to be associated with the T allele of dbSNP rs1415263. - Association with the RGS4 Gene on Chromosome 1q23 Mirnics et al. (2001) found that transcription of the regulator of G protein signaling-4 gene (602516) was decreased in a diagnosis-specific manner in patients with schizophrenia. To evaluate the possible role of RGS4 in schizophrenia, Chowdari et al. (2002) performed association and linkage studies on more than 1,400 ethnically diverse subjects with schizophrenia. They identified significant associations involving 4 SNPs (SNPs 1, 4, 7, and 18) within a 10-kb span of RGS4 on chromosome 1q23. Significant transmission distortion was observed at 2 of the SNPs, but with different alleles in 2 independent U.S. samples. Morris et al. (2004) sought to replicate the association study of Chowdari et al. (2002) in an independent Irish sample of schizophrenia cases and controls. They detected evidence of association at the RSG4 gene, and the signal came from a 4-marker haplotype reported by Chowdari et al. (2002). Similar to Chowdari et al., (2002) and Morris et al. (2004), Chen et al. (2004) genotyped samples from the Irish Study of High Density Schizophrenia Families using single marker transmission disequilibrium tests and haplotype analysis to RGS4 SNPs. Haplotype analyses suggested that the haplotype G-G-G for SNP1-4-18, which is the most abundant haplotype (42.3%) in the Irish families, was associated with narrow diagnosis schizophrenia (family-based association test (FBAT), p = 0.0061; pedigree disequilibrium test (PDT), p = 0.0498). Prasad et al. (2005) correlated the 4 SNPs in the RSG4 gene identified by Chowdari et al. (2002) with dorsolateral prefrontal cortex morphometry among 30 first-episode, antipsychotic-naive schizophrenia patients versus 27 control subjects. Robust volumetric differences across genotypes in the pooled sample of patients and control subjects were observed. When analyzed separately, the RGS4 polymorphisms were associated with morphometric differences within the patient group but not within the control group. The finding suggested that RGS4 polymorphisms may contribute to structural alterations in the dorsolateral prefrontal cortex of schizophrenia patients. Sobell et al. (2005) conducted a case-control analysis of 568 patients with schizophrenia and 689 controls and failed to confirm support for association of specific RGS4 SNP alleles or for association of a particular 4, 3, or 2 SNP haplotype. This study investigated the same SNPs and haplotypes found to be associated with schizophrenia in other studies. - Association with the CHI3L1 Gene on Chromosome 1q32 Using case-control and transmission/disequilibrium-test (TDT) methods, Zhao et al. (2007) detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 (601525) in 2 independent cohorts of Chinese individuals. The cohort for the case-control investigation consisted of 412 unrelated patients with schizophrenia and 464 control individuals; that for the TDT study, 308 unrelated probands with schizophrenia and their biologic parents. The at-risk CCC haplotype revealed lower transcriptional activity and was associated with lower expression compared with neutral and protective haplotypes. They found that an allele of SNP4 (dbSNP rs4950928), the tagging SNP of CCC, impaired the MYC/MAX (190080/154950)-regulated transcriptional activation of CHI3L1 by altering the transcription factor consensus sequences; Zhao et al. (2007) suggested that this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. The findings identified CHI3L1 as a potential schizophrenia susceptibility gene and suggested that the genes involved in the biologic response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia. - Association with the DISC1 Gene on Chromosome 1q42 See SCZD9 (604906). Ekelund et al. (2004) genotyped 300 polymorphic markers on chromosome 1 using a sample of 70 Finnish families with multiple individuals affected with schizophrenia or related conditions. They again found linkage on chromosome 1q42 maximizing within the DISC1 gene (dbSNP rs1000731, lod of 2.70). By analysis of SNPs and corresponding haplotypes across candidate genes in the 1q42 region identified by Ekelund et al. (2001) as being linked to schizophrenia in a Finnish sample, Hennah et al. (2003) identified a significant region of interest within the DISC1 gene. They identified a 2-SNP haplotype spanning from intron 1 to exon 2 of the DISC1 gene, designated HEP3 (605210.0001), and demonstrated that it was undertransmitted to affected women in the general Finnish population. The HEP3 haplotype also displayed sex differences in transmission distortion, the undertransmission being significant only in affected females. Hodgkinson et al. (2004) presented data from a case-control study of a North American white population, confirming the underrepresentation of the HEP3 haplotype in individuals with schizoaffective disorder. Multiple haplotypes contained within 4 haplotype blocks extending between exon 1 and exon 9 were associated with schizophrenia, schizoaffective disorder, and bipolar disorder. Hodgkinson et al. (2004) also found overrepresentation of a missense allele of the DISC1 gene, leu607 to pro, in schizoaffective disorder. These data supported the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders. - Association with the NRXN1 Gene on Chromosome 2p16.3 See SCZD17 (614322) for discussion of a possible association of susceptibility to schizophrenia with the NRXN1 gene (600565) on chromosome 2p16.3. - Association with the ZNF804A gene on Chromosome 2q31 O'Donovan et al. (2008) found evidence for an association of schizophrenia with a T allele at SNP dbSNP rs1344706 within the ZNF804A gene (612282) on chromosome 2q31. See SCZD14 (612361). - Association with the ERBB4 Gene on Chromosome 2q34 See 600543 for discussion of an association of susceptibility to schizophrenia with the ERBB4 gene on chromosome 2q34. - Association with the SYN2 Gene on Chromosome 3p25 Chen et al. (2004) reported positive association of synapsin II (600755) with schizophrenia in a case-control study. However, since case-control analyses can generate false-positive results in the presence of minor degrees of population stratification, Chen et al. (2004) performed a replication study in 366 additional Han Chinese probands and their parents by use of analyses of transmission/disequilibrium for 3 in/del markers and 3 single-nucleotide polymorphisms in the SYN2 gene on chromosome 3p25. Positive association was observed for dbSNP rs2307981, dbSNP rs2308169, dbSNP rs308963, dbSNP rs795009, and dbSNP rs2307973. For transmission of 6-marker haplotypes, a global P value of high significance was found. They concluded that this confirmed the previous study and provided further support for the role of synapsin II variants in susceptibility to schizophrenia. - De Novo Mutation in the ALS2CL Gene on Chromosome 3p21 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0901, an arg733-to-ter nonsense mutation was identified in the ALS2CL gene (612402) on chromosome 3p21. The mutation was predicted to result in the loss of the last 190 amino acids of the longest form of the protein. The authors noted that no nonsense mutations had been reported for this gene in SNP databases. - Association with the DRD3 Gene on Chromosome 3q13 See 126451 for discussion of a possible association of homozygosity for an allele of DRD3, on chromosome 3q13.3, with schizophrenia. - De Novo Mutation in the KPNA1 Gene on Chromosome 3q21 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0401, 2 nonsense mutations were identified. One was a glu448-to-ter mutation in the KPNA1 gene on chromosome 3q31 that was predicted to result in loss of the last 58 amino acids of the protein. The other was an arg480-to-ter mutation in the ZNF480 gene (613910) on chromosome 19q13 that was predicted to truncate the last 55 amino acids from the protein. The authors speculated that only one of these mutations might be pathogenic. - Association with the PMX2B Gene on Chromosome 4p13 Toyota et al. (2004) found that a subtype of strabismus (ocular misalignment), constant exotropia, displayed marked association with schizophrenia (p = 0.00000000906). They identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of the transcription factor gene PMX2B (603851), located on chromosome 4p13, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia as compared to control samples (p = 0.029). The polymorphisms were also associated with overall schizophrenia (p = 0.012) and more specifically with schizophrenia manifesting strabismus (p = 0.004). These results suggested a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. - De Novo Mutation in the SPATA5 Gene on Chromosome 4q28 By sequencing the exomes of 53 patients with sporadic schizophrenia, 22 unaffected controls, and their parents, Xu et al. (2011) identified 40 de novo mutations in 27 patients that affected 40 genes, including an amino acid deletion in the SPATA5 gene (613940) that was predicted to be damaging by PolyPhen-2. - Association with the CLINT1 Gene on Chromosome 5q33 See 607265 for discussion of a possible association of susceptibility to schizophrenia with the CLINT1 gene, also known as EPN4, on chromosome 5q33. Also see 181510. - Association with the DRD1 Gene on Chromosome 5q35.1 Allen et al. (2008) performed a metaanalysis comparing 725 patients with schizophrenia with 1,075 controls and found that the DRD1 -48A-G allele (126449; dbSNP rs4532) was associated with susceptibility to schizophrenia (odds ratio, 1.18; 95% CI, 1.01-1.38; p = 0.037). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the DRD1 association showed a 'strong' degree of epidemiologic credibility. - Association with the DTNBP1 Gene on Chromosome 6p22.3 See 607145 for discussion of a possible association of susceptibility to schizophrenia with the dystrobrevin-binding protein-1 gene on chromosome 6p22.3. Also see 600511. - Association with the NOTCH4 Gene on Chromosome 6p21 See 164951 for discussion of a possible association of polymorphisms in the NOTCH4 gene, on chromosome 6p21.3, with schizophrenia. - De Novo Mutation in the LAMA2 Gene on Chromosome 6q22 By sequencing the exomes of 53 patients with sporadic schizophrenia, 22 unaffected controls, and their parents, Xu et al. (2011) identified 40 de novo mutations in 27 patients that affected 40 genes, including a frameshift in the LAMA2 gene (156225) that was predicted to be damaging by PolyPhen-2. - Association with the TAAR6 (TRAR4) Gene on Chromosome 6q23 See 608923 for discussion of a possible association of susceptibility to schizophrenia with variation in the trace amine-associated receptor-6 gene on chromosome 6q23. Also see 603175. - Association with the AHI1 gene on chromosome 6q23 See 608894 for discussion of a possible association of susceptibility to schizophrenia with variation in the AHI1 gene on chromosome 6q23. Also see 603175. - Association with ABCA13 Gene on 7p12.3 Knight et al. (2009) reported evidence that ABCA13 (607807) is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, Knight et al. (2009) resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including 1 nonsense and 9 missense mutations and compound heterozygosity/homozygosity in 6 cases. Variants were genotyped in more than 1,600 additional schizophrenia, bipolar, depression cases and in more than 950 control cohorts, and the frequency of all rare variants combined was greater than controls in schizophrenia (odds ratio = 1.93, P = 0.0057) and bipolar disorder (odds ratio = 2.71, P = 0.00007). The population-attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, Knight et al. (2009) genotyped affected and unaffected relatives and found significant linkage (lod = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. Knight et al. (2009) concluded that their data identified a candidate gene (ABCA13), highlighted the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggested that rare coding variants may contribute significantly to risk of these disorders. - Association with the KCNH2 Gene on Chromosome 7q35-q36 See 152427 for discussion of a possible association of susceptibility to schizophrenia with variation in the KCNH2 gene on chromosome 7q35-q36. - Association with the VIPR2 Gene on Chromosome 7q36 See SCZD16 (613959) for a discussion of involvement of the VIPR2 gene (601970) in susceptibility to schizophrenia. - Association with the NRG1 Gene on Chromosome 8p22-p11 See 142445 for discussion of a possible association of susceptibility to schizophrenia with variation in the NRG1 gene on chromosome 8p22-p11. Also see 603013. - Association with the PPP3CC Gene on Chromosome 8p21.3 See 114107 for discussion of a possible association of susceptibility to schizophrenia with variation in the PPP3CC gene on chromosome 8p21.3. Also see 603013. - De Novo Mutation in the RB1CC1 Gene on Chromosome 8q11 By sequencing the exomes of 53 patients with sporadic schizophrenia, 22 unaffected controls, and their parents, Xu et al. (2011) identified 40 de novo mutations in 27 patients that affected 40 genes, including a frameshift in the RB1CC1 gene (606837) that was predicted to be damaging by PolyPhen-2. - Association with SLC1A1 Gene on Chromosome 9p24.2 See 133550 for discussion of a possible association of susceptibility to schizophenia-18 (SCZD18; 615232) with variation in the SLC1A1 gene on chromosome 9p24.2. - Association with SMARCA2 Gene on Chromosome 9p24.3 See 600014 for discussion of a possible association of susceptibility to schizophrenia with variation in the SMARCA2 gene on chromosome 9p24.3. - Association with the GRIN1 Gene on Chromosome 9q34 See 138249 for discussion of a possible association of susceptibility to schizophrenia with the N-methyl-D-aspartate receptor gene GRIN1 on chromosome 9q34.3. - Association with the TPH1 Gene on Chromosome 11p15.3-p14 Allen et al. (2008) performed a metaanalysis comparing 829 patients with schizophrenia with 1,268 controls across all ancestries and found that the TPH1 A versus C allele at position 218 in intron 7 (dbSNP rs1800532) of the TPH1 gene (191060) was associated with susceptibility to schizophrenia (OR, 1.31; 95% CI, 1.15-1.51; p less than 8(-5)). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the TPH1 association showed a 'strong' degree of epidemiologic credibility. - Association with the BDNF Gene on Chromosome 11p13 Neves-Pereira et al. (2005) studied the BDNF gene (113505) as a risk factor for schizophrenia in a Scottish population that included 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, 263 probands with a diagnosis of bipolar affective disorder, and 350 controls. The val66-to-met polymorphism (113505.0002) showed significant (p = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of the val/met SNP and a dinucleotide repeat polymorphism in the promoter region revealed highly significant (p less than 0.00000001) underrepresentation of the methionine (met1) haplotype in the schizophrenic but not the bipolar population. Therefore, the risk of this polymorphism may depend upon haplotypic background on which the val/met variant is carried. - Association with the DRD2 Gene on Chromosome 11q23 See 126450 for discussion of a possible association of schizophrenia susceptibility with polymorphisms in the DRD2 gene on chromosome 11q23. - De Novo Mutation in the ESAM Gene on Chromosome 11q24 By sequencing the exomes of 53 patients with sporadic schizophrenia, 22 unaffected controls, and their parents, Xu et al. (2011) identified 40 de novo mutations in 27 patients that affected 40 genes, including a frameshift in the ESAM gene (614281) that was predicted to be damaging by PolyPhen-2. - Association with the DAO Gene on Chromosome 12q24 See 124050 for discussion of a possible association of schizophrenia susceptibility with polymorphisms in the D-amino acid oxidase gene on chromosome 12q24. - De Novo Mutation in the LRP1 Gene on Chromosome 12q13 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0201, 2 mutations were identified. One was a tyr2200-to-ter nonsense mutation in the LRP1 gene (107770) on chromosome 12q13, which was predicted to truncate the protein to half of its normal size. The other mutation occurred in the CCDC137 gene (614271) on chromosome 17q25. - Association with the NOS1 Gene on Chromosome 12q24 See 163731 for discussion of a possible association of schizophrenia susceptibility with polymorphisms in the NOS1 gene on chromosome 12q24. - Association with the HTR2A Gene on Chromosome 13q32 See 182135 for discussion of the association of susceptibility to schizophrenia with polymorphisms in the serotonin 5-HT-2A receptor gene on chromosome 13q32. Also see 607176. - Association with the G72 (DAOA) Gene on Chromosome 13q34 See 607408 for discussion of a possible association of schizophrenia susceptibility with polymorphisms in the G72 gene on chromosome 13q34. Also see 607176. - Association with the GPHN gene on Chromosome 14q23 See 603930 for discussion of a possible association of schizophrenia susceptibility with variation in the GPHN gene (603930) on chromosome 14q23. - Association with the AKT1 Gene on Chromosome 14q32 See 164730 for discussion of a possible association of schizophrenia susceptibility with polymorphisms in the AKT1 gene on chromosome 14q32. - Association with the CHRNA7 Gene on Chromosome 15q14 See 118511 for discussion of a possible schizophrenia susceptibility locus on chromosome 15q14 associated with the gene for subunit 7 of the nicotinic acetylcholine receptor. - Association with the YWHAE Gene on Chromosome 17p13 Among 1,429 Japanese patients with schizophrenia and 1,728 controls, Ikeda et al. (2008) found a significant association between a G-to-C SNP (dbSNP rs28365859) in the 5-prime flanking region of the YWHAE gene (605066), -261 bp from the initial exon, and schizophrenia. Controls had a significantly higher frequency of the minor C allele compared to patients (p = 1.01 x 10(-5)). The region where this SNP is located is not highly conserved. In vitro functional expression studies showed that the minor C allele was associated with higher gene expression, and YWHAE mRNA and protein levels were higher in peripheral blood samples of C allele carriers compared to G allele carriers. An odds ratio of 0.76 was associated with the C allele, suggesting a protective effect. Ikeda et al. (2008) demonstrated that heterozygous Ywhae mice had weak defects in working memory and increased anxiety-like behavior. Overall, the findings suggested that YWHAE may be a susceptibility gene for schizophrenia. The YWHAE gene was studied because of its interaction with DISC1 (605210), which has been implicated in schizophrenia. - Association with the SLC6A4 Gene on Chromosome 17q11-q12 See 182138 for discussion of a possible association of schizophrenia susceptibility with the SLC6A4 gene on chromosome 17q11-q12. - De Novo Mutation in the CCDC137 Gene on Chromosome 17q25 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0201, 2 mutations were identified. One was a tyr125-to-cys mutation in the CCDC137 gene (614271) on chromosome 17q25, which was predicted to be damaging by 4 prediction algorithms. The other mutation occurred in the LRP1 gene (107770) on chromosome 12q13. - Association with the GNAL Gene on Chromosome 18p See 139312 for discussion of a possible association of schizophrenia susceptibility with the GNAL gene on chromosome 18p. Also see SCZD6 (603206). - Association with the C3 Gene on Chromosome 19p13 Rudduck et al. (1985) found that a complement component C3 subtype (120700), which maps to 19p13, was significantly increased among individuals with schizophrenia. - Association with the APOE Gene on Chromosome 19q13 In a study of apolipoprotein E (107741) genotypes in schizophrenic patients coming to autopsy, Harrington et al. (1995) found that schizophrenia is associated with an increased E4 allele frequency. The E4 allele frequency in schizophrenia was indistinguishable from that found in either Alzheimer disease (see 104300) or Lewy body dementia (127750). From the age range at autopsy (19 to 95 years), they determined that the E4 frequency was not associated with increased age. - De Novo Mutation in the ZNF565 Gene on Chromosome 19q13 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of the 15 identified de novo mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0101, 2 different de novo missense mutations were identified. One was a his385-to-arg mutation in the ZNF565 gene (614275) on chromosome 19q13. The mutation occurred in a conserved amino acid and read as possibly damaging and damaging by PolyPhen and SIFT, respectively. The other mutation occurred in the NRIP1 gene (602490) on chromosome 21q11. - De Novo Mutation in the ZNF480 Gene on Chromosome 19q13 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0401, 2 nonsense mutations were identified. One was an arg480-to-ter mutation in the ZNF480 gene (613910) on chromosome 19q13 that was predicted to truncate the last 55 amino acids from the protein. The other was a glu448-to-ter mutation in the KPNA1 gene on chromosome 3q31 that was predicted to result in loss of the last 58 amino acids of the protein. The authors speculated that only one of these mutations might be pathogenic. - De Novo Mutation in the CHD4 Gene on Chromosome 20q13 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ1001, an arg576-to-trp mutation was identified in the CDH4 gene (603006) on chromosome 20q13, which was predicted to be damaging by 4 prediction algorithms. - De Novo Mutation in the NRIP1 Gene on Chromosome 21q11 Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which was significantly more than expected considering the previously reported de novo mutation (DNM) rate. In addition, 4 of these mutations were nonsense mutations, which was more than what was expected by chance. In patient SCZ0101, 2 different de novo missense mutations were identified. One was a lys722-to-thr mutation in the NRIP1 gene (602490), The mutation read as probably damaging and damaging by PolyPhen and SIFT, respectively. The other mutation occurred in the ZNF565 gene (614275) on chromosome 19q13. - Association with the OLIG2 Gene on Chromosome 21q22 Georgieva et al. (2006) and Huang et al. (2008) independently observed an association between schizophrenia and several SNPs in the OLIG2 gene (606386), including dbSNP rs1059004 and dbSNP rs762178 in Caucasian and Chinese Han patients, respectively. Huang et al. (2008) also found a significant disease association with a haplotype defined by the A and T alleles of these 2 SNPs, respectively (p = 0.009 after Bonferroni correction). - Association with the COMT Gene on Chromosome 22q11 Several lines of evidence had implicated the catechol-O-methyltransferase gene (116790) gene as the candidate gene for schizophrenia. One of these was its biochemical function and metabolism of catecholamine neurotransmitters; another was the microdeletion on 22q11 that includes the COMT gene and causes velocardiofacial syndrome (192430), a syndrome associated with a high rate of psychosis, particularly schizophrenia. Shifman et al. (2002) reported the results of a study of COMT as a candidate gene for schizophrenia, using a large sample size (the largest case-control study performed to that time); a relatively well-defined and homogeneous population (Ashkenazi Jews); and a stepwise procedure in which several single nucleotide polymorphisms (SNPs) were scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. They found a highly significant association between schizophrenia and a COMT haplotype; p = 9.5 x 10(-8). Glatt et al. (2003) evaluated the collective evidence for an association between the COMT val158/108met polymorphism (116790.0001; codon 158 of the membrane-bound form; codon 108 of the soluble form) of the COMT gene and schizophrenia by performing a separate metaanalysis of 14 case-control and 5 family-based studies published between 1996 and 2002. Overall, the case-control studies showed no indication of an association between either allele and schizophrenia, but the family-based studies found modest evidence implicating the val allele in schizophrenia risk. Glatt et al. (2003) concluded that the family-based studies might be more accurate since this method avoids the pitfalls of population stratification. They suggested that the val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry but that its role in Asian populations remained unclear. Fan et al. (2005) conducted a large-scale association study plus a metaanalysis of the COMT val/met polymorphism and risk of schizophrenia in 862 patients and 928 healthy control subjects from a Han Chinese population. No significant differences were found in allele or genotype frequencies between patients and normal control subjects, although a nonsignificant overrepresentation of the val allele in schizophrenia patients (OR, 1.09, 95% CI, 0.94-1.26) was suggested. The metaanalysis provided no significant evidence for an association between schizophrenia and the val allele in Asian or European populations. - Association with the ZDHHC8 Gene on Chromosome 22q11 Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-Mb region of 22q11 associated with susceptibility to schizophrenia (Karayiorgou et al., 1995; Bassett et al., 2003), Liu et al. (2002, 2002) identified 2 subregions that were consistently associated with the disease. In the distal subregion, they detected an association signal with 5 neighboring SNPs distributed over a haplotype block of 80 kb encompassing 6 known genes. One of these 5 SNPs, an A/G polymorphism (dbSNP rs175174) in intron 4 of the ZDHHC8 gene (608784), had the strongest association of all 72 SNPs tested. Mukai et al. (2004) showed that dbSNP rs175174 regulated the level of the fully functional transcript by modulating the retention of intron 4 of the ZDHHC8 gene, which encodes a putative transmembrane palmitoyltransferase. Zdhhc8 knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in a new environment, and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine. In humans, the SNP showed differences in transmission distortion between sexes in individuals with schizophrenia. In an extended sample of 389 families from the U.S. and South Africa, transmission distortion was significant in females (transmitted:untransmitted ratio = 82:43) but not in males (transmitted:untransmitted ratio = 106:108). Mukai et al. (2004) suggested that the sexually dimorphic effect of ZDHHC8 in schizophrenia might be related to the observed sex differences in onset, incidence, and severity course of schizophrenia. In a Han Chinese population, Chen et al. (2004) showed that the G allele of the ZDHHC8 A/G SNP was significantly more common in schizophrenics than in controls; excess transmission of the same allele was confirmed by the family-based transmission disequilibrium test. Glaser et al. (2005) investigated the ZDHHC8 putative risk allele dbSNP rs175174 in 4 schizophrenia-associated samples: a Bulgarian proband and parent sample (474 trios) and 3 case-control panels of European origin (1,028 patients/1,253 controls). The results did not support the hypothesis that genetic variation in this allele is associated with increased risk for schizophrenia nor did they suggest the presence of gender-specific differences. - Association with the PRODH Gene on Chromosome 22q11 Li et al. (2004) analyzed the PRODH gene in patients with schizophrenia and their families from Sichuan Province in China, comprising 528 family trios and sib pairs. They found association of schizophrenia with 2 haplotypes consisting of the 1945T-C and 1852G-A variants (global p = 0.006) and the 1852G-A and 1766A-G variants (global p = 0.01). - Association with the RTN4R Gene on Chromosome 22q11 Sinibaldi et al. (2004) identified mutations in the RTN4R gene (605566.0001-605566.0002) on chromosome 22q11 in Italian patients with schizophrenia. - De Novo Mutation in the DGCR2 Gene on Chromosome 22q11 By sequencing the exomes of 53 patients with sporadic schizophrenia, 22 unaffected controls, and their parents, Xu et al. (2011) identified 40 de novo mutations in 27 patients that affected 40 genes, including a potentially disruptive mutation in DGCR2 (600594), a gene located in the schizophrenia-predisposing 22q11.2 microdeletion region. - Association with the SHANK3 gene on Chromosome 22q13 Gauthier et al. (2010) identified mutations in the SHANK3 gene (606230.0002-606230.0003) on chromosome 22q13 in northern European patients with schizophrenia. - Association with CAG/CTG Repeats Tsutsumi et al. (2004) used a repeat expansion detection assay to examine genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. They found that 28% of probands with schizophrenia and 38% of probands with bipolar disorder had CAG/CTG repeats in the expanded range. Each expansion could be explained by 1 of 3 nonpathogenic repeat expansions known to exist in the general population. Thus, novel CAG/CTG repeat expansions were not a common genetic risk factor for bipolar disorder or schizophrenia in this study. - Epigenetic Theory of Major Psychosis Epigenetic misregulation is consistent with various nonmendelian features of schizophrenia and bipolar disorder (125480). Mill et al. (2008) used CpG island microarrays to identify DNA methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex they found evidence for psychosis-associated DNA methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA methylation changes in a significant proportion of these loci corresponded to reported changes of steady-state mRNA levels associated with psychosis. Gene ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Methylome network analysis uncovered decreased epigenetic modularity in both the brain and the germline of affected individuals, suggesting that systemic epigenetic dysfunction may be associated with major psychosis. Mill et al. (2008) also reported evidence for a strong correlation between DNA methylation in the promoter region of the MEK1 gene (176872) and lifetime antipsychotic use in schizophrenia patients. Finally, they observed that frontal cortex DNA methylation in the BDNF gene (113505) was correlated with genotype at a nearby nonsynonymous SNP (V66M) that had been associated with major psychosis. They considered the data to be consistent with the epigenetic theory of major psychosis and suggested that DNA methylation changes are important to the etiology of schizophrenia and bipolar disorder. - Novel De Novo Point Mutations Girard et al. (2011) sequenced the exomes of 14 schizophrenia probands and identified 15 de novo mutations in 8 probands, which is significantly more than expected considering the previously reported DNM rate. In addition, 4 of the 15 identified de novo mutations are nonsense mutations, which is more than what is expected by chance. In 1 patient, SCZ0101, 2 different de novo mutations were identified, a missense mutation in the ZNF565 gene (his385 to arg). This was found to be a conserved amino acid and read as possibly damaging and damaging by PolyPhen and SIFT, respectively. The second mutation was in the NRIP1 gene (602490); a missense mutation, lys722-to-thr. This was read as moderately conservative, probably damaging, and damaging. Patient SCZ0201 also had 2 de novo mutations; 1 in the LRP1 gene (107770), a tyrosine to termination substitution at codon 2200,. and in the CCDC137 gene, a tyrosine to cysteine substitution at codon 125. This was read as probably damaging and damaging by PolyPhen and SIFT. Patient SCZ0401 also had 2 mutations; 1 in KPNA1 (600686), a nonsense mutation, glu448 to ter; the patient's second mutation was also a nonsense mutation in the ZNF480 gene (613910), an arg480 to ter mutation. Patient SCZ0901 had a nonsense mutation in the ALS2CL gene (612402), an arg-to-ter at codon 733. There were 3 other likely damaging mutations reported: 1 in SCZ1001 in the CHD4 gene (603006), a G-to-A transition at genomic position 6,707,226, resulting in an arg-to-trp substitution at codon 576. This patient had a second missense mutation in the KDM2B gene (609078), a C-to-T transition at position 121,882,033, resulting in a gly-to-ser substitution at codon 745, and a third mutation in the LAMA1 gene (150320), a T-to-C transition at nucleotide 6,974,966, resulting in a thr-to-ala substitution at codon 2187. Xu et al. (2011) independently sequenced the exomes of 53 sporadic cases, 22 unaffected controls, and their parents. Xu et al. (2011) identified 40 de novo mutations in 27 cases affecting 40 genes, including a potentially disruptive mutation in DGCR2 (600594), a gene located in the schizophrenia predisposing 22q11.2 microdeletion region. A comparison to rare inherited variants indicated that the identified de novo mutations show a large excess of nonsynonymous changes in schizophrenia cases, as well as a greater potential to affect protein structure and function. Xu et al. (2011) concluded that their analyses suggest a major role for de novo mutations in schizophrenia as well as a large mutational target, which together provide a plausible explanation for the high global incidence and persistence of the disease. Mutations in 4 genes, SPATA5 (613940), RB1CC1 (606837), LAMA2 (156225), and ESAM (614281), were predicted to be damaging by PolyPhen-2.
If a narrow diagnostic definition is used, the lifetime morbid risk of schizophrenia does not vary far from 1% (range 0.7-1.4%) in a wide variety of geographic regions (Jablensky et al., 1992). A higher incidence has been found ... If a narrow diagnostic definition is used, the lifetime morbid risk of schizophrenia does not vary far from 1% (range 0.7-1.4%) in a wide variety of geographic regions (Jablensky et al., 1992). A higher incidence has been found in certain populations (Book et al., 1978).