Alternative titles; symbols
SNOMEDCT: 191526005, 58214004; ICD10CM: F20, F20.9; ICD9CM: 295, 295.9, 295.90; DO: 5419;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.2 | {Schizophrenia 12} | 181500 | Autosomal dominant | 2 | SCZD12 | 608543 |
| 1p36.22 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | MTHFR | 607093 |
| 1q32.1 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | CHI3L1 | 601525 |
| 1q42.2 | Schizophrenia | 181500 | Autosomal dominant | 2 | DISC2 | 606271 |
| 3p25.2 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | SYN2 | 600755 |
| 3q13.31 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | DRD3 | 126451 |
| 5q23-q35 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD1 | 181510 |
| 6p23 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD3 | 600511 |
| 6q13-q26 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD5 | 603175 |
| 8p21 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD6 | 603013 |
| 10q22.3 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD11 | 608078 |
| 11q14-q21 | {?Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD2 | 603342 |
| 13q14.2 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | HTR2A | 182135 |
| 13q32 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD7 | 603176 |
| 13q33.2 | {Schizophrenia} | 181500 | Autosomal dominant | 2 | DAOA | 607408 |
| 18p | {Schizophrenia} | 181500 | Autosomal dominant | 2 | SCZD8 | 603206 |
| 22q11.21 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | COMT | 116790 |
| 22q11.21 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 | RTN4R | 605566 |
| 22q12.3 | {Schizophrenia} | 181500 | Autosomal dominant | 1 | APOL4 | 607254 |
| 22q12.3 | {Schizophrenia} | 181500 | Autosomal dominant | 1 | APOL2 | 607252 |
A number sign (#) is used with this entry because multiple gene loci are involved in the causation of this complex trait. Other entries describe schizophrenia susceptibility loci that have been identified or are suspected from linkage or association studies or chromosomal aberrations.
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.
Schizophrenia and bipolar disorder (see 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).
Genetic Heterogeneity of Schizophrenia with or without an Affective Disorder
SCZD4 (600850) is associated with variation in the PRODH gene (606810); SCZD9 (604906) with variation in the DISC1 gene (605210); SCZD15 (613950) with variation in the SHANK3 gene (606230); SCZD16 (613959) with a chromosome duplication involving the VIPR2 gene (601970); SCZD17 (see 614332) with variation in the NRXN1 gene (600565); SCZD18 (615232) with variation in the SLC1A1 gene (133550); and SCZD19 (617629) with variation in the RBM12 gene (607179).
For associations pending confirmation, see MAPPING and MOLECULAR GENETICS.
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 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. It often develops in young adults who were previously normal (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.
Vawter et al. (1998) found a selective increase in the level of 105- to 115-kD NCAM (116930) in hippocampal homogenates from postmortem brains from patients with schizophrenia compared to those from normal controls and from patients with bipolar disease.
Futamura et al. (2002) measured epidermal growth factor (EGF; 131530) protein levels in postmortem brains and in fresh serum of patients with schizophrenia and control subjects. In the patients, EGF protein levels were decreased in the prefrontal cortex and striatum, and EGF receptor (131550) expression was elevated in the prefrontal cortex. Serum EGF levels were reduced, even in young, drug-free patients. Futamura et al. (2002) found that chronic treatment of rats with haloperidol had no influence on EGF levels in the brain or serum. Futamura et al. (2002) suggested that there is abnormal EGF production in central and peripheral tissues in patients with schizophrenia.
Schizophrenia appears to have a significant genetic component. Multiple studies have consistently demonstrated that the risk to relatives of a proband with schizophrenia is higher than that to relatives of controls (Kendler and Diehl, 1985). Moldin (1998) reviewed family and twin studies published between 1920 and 1987 and found the recurrence risk ratios to be 48 for monozygotic twins, 11 for first-degree relatives, 4.25 for second-degree relatives, and 2 for third-degree relatives. He also found that concordance rates for monozygotic twins averaged 46%, even when reared in different families, whereas the concordance rates for dizygotic twins averaged only 14%. The prevalence of schizophrenia is higher in biologic than in adoptive relatives of schizophrenic adoptees (Gottesman, 1991).
In an epidemiologic study in rural Ireland, Waddington and Youssef (1996) found that the risk for schizophrenia among first-degree relatives of probands was 6.1% and that the risk among sibs was 8.3%, exceeding that among their parents (1.4%).
Although the importance of genetic factors and the distinctness from manic-depressive psychosis are indicated by twin studies, the mode of inheritance is unclear. Some (e.g., Garrone, 1962) suggested recessive inheritance. Others (e.g., Book, 1953; Slater, 1958) favored irregular dominant inheritance. A priori, polygenic inheritance seems most likely, according to the rule that relatively frequent disorders such as this do not have simple monomeric genetic determination. Within the larger group, there may be entities that behave in a simple mendelian manner. Heston (1970) reviewed the evidence and concluded that it supports the autosomal dominant hypothesis. He pointed out that the definition of schizophrenia used by researchers is a broad one encompassing the schizoid state, the 'schizophrenic spectrum.' Schizoid disease and schizophrenia occur with about equal frequency among the cotwins of schizophrenic monozygotic twin probands, bringing the concordance rate close to 100%. About 45% of sibs, parents, and offspring of schizophrenics have schizoid disease or schizophrenia, as are about 66% of children who have 2 parents with schizophrenia. About 4% of the general population is affected with schizoid-schizophrenic disease. See editorial review in Lancet (Anonymous, 1970). Kidd and Cavalli-Sforza (1973) favored recessive inheritance.
Risch and Baron (1984) concluded that either a polygenic or a mixed model (with a single major locus making a major contribution to genetic liability) gives good agreement with segregation analysis of family data and is consistent with supplementary observations (lifetime disease incidences, mating-type distribution, and monozygotic twin concordance). For a polygenic model, the estimated components of variance were polygenes (H), 81.9%; common sib environment (B), 6.9%; and random environment (R), 11.2%. They concluded that in the mixed model the postulated single locus is more likely to be recessive than dominant, with a high frequency and low penetrance. The most likely recessive mixed model gave the following partition of liability variance: major locus, 62.9%; polygenes, 19.5%; common sib environment, 6.6%; and random environment, 11%. Murray et al. (1985) reviewed genetic studies of schizophrenia and suggested heterogeneity. They stated that familial cases will be the most valuable for molecular genetic study. Consideration of pooled Western European studies led to an estimate of either 2 or 3 epistatic loci (Risch, 1990).
Stober et al. (1995) conducted a family study of 139 probands who met DSM-III-R catatonic schizophrenia conditions and 543 first-degree relatives. They found an age-corrected morbidity risk of 4.6% in systematic catatonia and 26.9% age-corrected morbidity risk in periodic catatonia. They contended that this pointed strongly to a major gene effect in periodic catatonia.
Stober et al. (1995) performed a pairwise comparison of age of onset between affected probands and parents that demonstrated anticipation which was even more strikingly apparent in pedigrees with 3 successive generations affected. They suggested that there may be a major gene with trinucleotide repeat expansions or other repetitive elements affecting gene expression responsible for many cases of periodic catatonia. See also SCZD1 (181510).
Bassett and Husted (1997) noted several studies that observed anticipation (earlier age at onset in successive generations) in familial schizophrenia (Bassett and Honer, 1994; Asherson et al., 1994). In 1944, while he was working in Ontario because of his status as a conscientious objector during World War II, Lionel S. Penrose collected anticipation data on a large, representative sample of familial mental illness, using a broad ascertainment strategy (Penrose, 1991). Bassett and Husted (1997) used these data to examine anticipation and ascertainment biases in five 2-generation samples of affected relative pairs. The median intergenerational difference (MID) in age at onset was used to assess anticipation. Results showed significant anticipation in parent-offspring pairs with schizophrenia and in a positive control sample with Huntington disease (143100). Broadening the diagnosis of the schizophrenia sample suggested anticipation of severity of illness. However, other analyses provided evidence for ascertainment bias, especially in later-age-at-onset parents, in parent-offspring pairs. Aunt/uncle-niece/nephew schizophrenia pairs showed anticipation, but the MID was 8 years and aunts/uncles had earlier median age at onset than parents. Bassett and Husted (1997) interpreted the findings as suggesting that although the effects of ascertainment bias were observed in parent-offspring pairs, true anticipation appears to be inherent in the transmission of familial schizophrenia. The findings supported investigations of unstable mutations and other mechanisms that might contribute to true anticipation in schizophrenia.
Rh incompatibility had been implicated as a risk factor for schizophrenia. Hollister et al. (1996) found that the proportion of Rh-incompatible male offspring (2.1%) was significantly larger than the proportion of Rh-compatible male offspring (0.8%), yielding a relative risk of 2.78. Palmer et al. (2002) assessed the role of maternal-fetal genotype incompatibility at the RHD locus (111680) in schizophrenia. They sought to determine whether the effect of the RHD locus results from a maternal-fetal genotype incompatibility, from linkage and association with a high-risk susceptibility allele at or near the RHD locus, or from the effects of the maternal genotype acting alone. They studied 88 patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs with genotyping at the RHD locus. There was significant evidence for an RHD maternal-fetal genotype incompatibility. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus and no evidence to support the role of maternal genotype effect alone.
Awadalla et al. (2010) hypothesized that deleterious de novo mutations may play a role in cases of autism spectrum disorders (ASD; 209850) and schizophrenia, 2 etiologically heterogeneous disorders with significantly reduced reproductive fitness. Awadalla et al. (2010) presented a direct measure of the de novo mutation rate (mu) and selective constraints from de novo mutations estimated from a deep resequencing dataset generated from a large cohort of ASD and schizophrenia cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of approximately 430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate de novo mutations, 13 of which were cell line artifacts. Awadalla et al. (2010) calculated a direct neutral mutation rate (1.36 x 10(-8)) that was similar to previous indirect estimates, but they observed a significant excess of potentially deleterious de novo mutations in ASD and schizophrenia individuals. Awadalla et al. (2010) concluded that their results emphasized the importance of de novo mutations as genetic mechanisms in ASD and schizophrenia and the limitations of using DNA from archived cell lines to identify functional variants.
The choice of diagnostic criteria of schizophrenia for genetic studies can be difficult. However, interrater reliability for the diagnosis of schizophrenia is excellent, with estimates of kappa ranging from 0.76 to 0.82 and measurements of test-retest reliability from 0.68 to 0.79 (Regier et al., 1994).
For genetic studies, difficulties arise in defining appropriate boundaries from what are classified in the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM) as distinct but similar disorders. These include psychoses such as schizoaffective, schizotypal, schizophreniform and delusional disorders, and personality disorders such as schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder (Flaum et al., 1997; Farmer et al., 1991).
Leonhard (1979) classified schizophrenia as existing in systematic and unsystematic forms, based on different types of symptoms, the long-term course, and the outcome. Stober et al. (1995) considered Leonhard's classification to be highly valid and reliable. They referred to his distinction between periodic catatonia and systematic catatonia and extended his observation. Periodic catatonia is one clinical subtype of unsystematic schizophrenia in Leonhard's classification. The typical course is bipolar with both hyperkinetic and akinetic states, in which symptoms of 1 pole are mingled with those of the other. In this form, there are grimaces, parakinetic movements, stereotypes, and impulsive actions with aggressiveness, as well as negativistic behavior. After an initially remittent course with one or more attacks, there develops a residual state with increasing poverty of movements, blunted affects, and lack of motivation. Systematic catatonia, in contrast, begins insidiously and runs a chronic progressive course without remissions. Leonhard (1979) had found that individuals with systematic catatonia had a positive family history with regard to schizophrenia in 3 to 4% of individuals, whereas approximately 20% of patients with periodic catatonia had family members with psychosis.
McGuffin et al. (1987) concluded that although the clinical presentation and course of schizophrenia is highly variable, the evidence of fundamental genetic heterogeneity or division into genetic and nongenetic forms is minimal. They stated: 'It seems improbable that any further useful and genetically relevant subdivision of schizophrenia can be effected on purely clinical grounds.' They suggested that further developments will depend on the application of molecular genetic marker strategies and on the discovery of endophenotypes. (Endophenotypes is an interesting, potentially useful term, the meaning of which is probably evident from the context.)
Ilani et al. (2001) found a correlation between the D3 dopamine receptor (DRD3; 126451) on peripheral blood lymphocytes and schizophrenia and suggested that increased D3 receptor mRNA on blood lymphocytes may be a useful marker for identification and follow-up of schizophrenia.
Eye movement disturbances have been suggested as a phenotypic marker for schizophrenia (Holzman, 2000). Rybakowski et al. (2001) found an association between eye movement disturbances and the ser9 polymorphism (126451.0001) in the DRD3 gene. They suggested that the DRD3 polymorphism may be a contributing factor to the eye movement disturbances in schizophrenia.
Schizophrenia is treated chiefly with dopamine antagonists. Atypical antipsychotic drugs such as clozapine have been introduced in an effort to avoid extrapyramidal side effects resulting from prolonged use of dopamine antagonists.
Basile et al. (2002) discussed the role of genetic polymorphisms in predicting responsiveness to pharmacotherapeutic agents in schizophrenia. They focused on genetic variants in the dopamine receptor genes and clinical response to clozapine.
Lencz et al. (2006) examined the response of 61 first-episode schizophrenia patients with reference to 2 promoter region SNPs (241A-G and -141ins/del)C of the DRD2 gene (126450). Patients meeting selection criteria were randomized to receive 16 weeks of treatment with either risperidone or olanzapine. Time until sustained response (2 consecutive ratings without significant positive symptoms) for the rare allele carriers versus wildtype allele was examined using Kaplan-Meier curves. Carriers with the rarer -241A allele exhibited a significantly faster time until response (log-rank = 8.40, df = 1, p less than 0.004) and the -141delC carriers took significantly longer (log-rank = 5.03, df = 1, p less than 0.03) to respond, suggesting that variation in the DRD2 receptor gene can partially explain variation in the timing of clinical response to antipsychotics in the first episode of schizophrenia.
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).
Gulsuner et al. (2020) studied schizophrenia in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, GABA, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed the understanding of the genetics of schizophrenia worldwide.
Chodirker et al. (1987) reported a family in which the karyotypes of 4 brothers demonstrated a fragile site at 19p13. Two of the brothers had schizophrenia, 1 had mental retardation with autistic behavior, and 1 was phenotypically normal.
See dopamine receptor D2 (DRD2; 126450) for a description of chromosomal abnormalities of 11q associated with schizophrenia.
Kamnasaran et al. (2003) reported a mother and daughter with schizophrenia who were carriers of a t(9;14)(q34;q13) chromosome. No genes were disrupted at the breakpoint on chromosome 9, but the breakpoint on chromosome 14q12 occurred within intron 3 of the NPAS3 gene (609430), affecting the coding region of both alternative transcripts. The daughter, who was more severely affected, also had microdeletions within intron 2 of the NPAS3 gene and within intron 3 of a proximal gene, KIAA0391 (609947). Both of these intronic regions contain several possible transcription factor-binding sites.
Knight et al. (2009) identified a complex chromosomal rearrangement, inv(7)(p12.3;q21.11),t(7;8)(p12.3;p23) in a 48-year-old male who had a diagnosis of severe chronic schizophrenia with continuous symptoms since first admission to psychiatric hospital at the age of 16. After an initial series of inpatient stays, he was continuously in the hospital for more than 25 years.
Linkage Studies for Complex Traits
Elston et al. (1973) attempted to demonstrate the operation of single genes through linkage studies. Feder et al. (1985) used 2 approaches to test the possible implication of the POMC gene on chromosome 2p in schizophrenia and bipolar affective illness. Both yielded negative results. The first method involved testing normal controls and patients with a variety of restriction enzymes to detect a difference due to a single nucleotide substitution that is directly responsible for the disease state. The second approach, using linkage disequilibrium, made use of DNA polymorphisms so close to the POMC gene that association would be found if a POMC mutation were responsible for all or many of the cases of either psychiatric disease. The use of the DNA markers for linkage in specific pedigrees is limited by the low penetrance and uncertain mode of inheritance.
Gershon et al. (1990) reviewed the linkage studies and pointed out that 'none of these linkage reports is uncontested.' They continued: 'Nonetheless, it appears promising to continue attempts to map these psychiatric disorders, since linkage can now be detected even when the inheritance is complex and includes genetic heterogeneity and variable penetrance.'
Susceptibility Loci Mapped by Linkage and/or Association Studies
See SCZD1 (181510) for discussion of a schizophrenia susceptibility locus on chromosome 5.
See SCZD2 (603342) for discussion of a schizophrenia susceptibility locus on chromosome 11q.
See SCZD3 (600511) for discussion of schizophrenia susceptibility loci on chromosome 6.
See SCZD5 (603175) for discussion of a schizophrenia susceptibility locus on chromosome 6q.
See SCZD6 (603013) for discussion of a schizophrenia susceptibility locus on chromosome 8p22-p21. Genomewide scans in several populations have mapped a schizophrenia locus to 8p.
See SCZD7 (603176) for discussion of a schizophrenia susceptibility locus on chromosome 13q32.
See SCZD8 (603206) for discussion of a schizophrenia susceptibility locus on chromosome 18p.
See SCZD10 (605419) for discussion of a schizophrenia susceptibility locus (periodic catatonia) on chromosome 15q15.
See SCZD11 (608078) for discussion of a schizophrenia susceptibility locus on chromosome 10q22.
See SCZD12 (608543) for discussion of a schizophrenia susceptibility locus on chromosome 1p.
See SCZD13 (613025) for discussion of a schizophrenia susceptibility locus on chromosome 15q13-q14.
See SCZD14 (612361) for discussion of a schizophrenia susceptibility locus on chromosome 2q32.1.
Genomewide Linkage or Association Studies
DeLisi et al. (2002) conducted a genomewide scan of 382 sib pairs with the diagnosis of schizophrenia or schizoaffective disorder collected at 5 centers between 1985 and 2002. Using 396 highly polymorphic markers placed approximately 10 cM apart throughout the genome, they obtained the highest multipoint nonparametric lod scores at 10p15-p13 (maximum lod = 3.60 at D10S189), in the pericentromeric region of chromosome 2 (maximum lod = 2.99 at D2S139), and at 22q12 (maximum lod = 2.00 at D22S283). The 22q12 locus showed evidence of imprinting with excess sharing of maternal alleles. No evidence of linkage was found at 9 previously identified locations. DeLisi et al. (2002) concluded that this study revealed the weakness of linkage reports on schizophrenia. They noted that no linkage has consistently been replicable across large studies. Nonetheless, they suggested that the positive findings on chromosomes 2, 10, and 22 should be pursued.
Coon et al. (1993) could find no evidence of genetic linkage of any 1 of 5 dopamine receptor genes to schizophrenia in 9 multigenerational families that included multiple affected persons. The 5 loci tested were all on different chromosomes: DRD1 (126449), DRD2 (126450), DRD3 (126451), DRD4 (126452), and DRD5 (126453).
The X chromosome has been implicated in several studies of schizophrenia. Delisi et al. (1991) could find no evidence of linkage of schizophrenia to markers on Xq27-q28 in studies of 10 multiplex families. On the other hand, in studies of 83 sibships with 2 or more sibs fulfilling diagnostic criteria for schizophrenia or schizoaffective disorder, Collinge et al. (1991) found that affected sibs shared alleles at the DXYS14 locus more frequently than expected by random mendelian assortment. Since DXYS14 is located on the pseudoautosomal telomeric portion of the X chromosome and is unlinked with sex, the finding supports genetic linkage of the marker and schizophrenia. Crow (1988) had suggested that a pseudoautosomal locus might be involved because of a reported excess of sex-chromosome aneuploidies (e.g., XXY and XXX) among patients with schizophrenia and the finding that schizophrenic sib pairs are more often of the same sex than of different sex.
Williams et al. (1999) undertook a systematic search for linkage in 196 affected sib pairs (ASPs) with schizophrenia. In stage 1 of a 2-stage approach, they typed 97 ASPs with 229 microsatellite markers at an average intermarker distance of 17.26 cM. Multipoint affected sib pair analysis identified 7 regions with a maximum lod score (MLS) at or above the level associated with a nominal pointwise significance of 5% on a total of 7 chromosomes. In stage 2, they genotyped a further 54 markers in 196 ASPs together with parents and unaffected sibs. This allowed the regions identified in stage 1 to be typed at an average spacing of 5.15 cM, while the region of interest on chromosome 2 was typed to 9.55 cM. Simulation studies suggested that one would expect 1 multipoint MLS of 1.5 per genome scan in the absence of linkage. An MLS of 3 would be expected only once in every 20 genome scans and thus corresponded to a genomewide significance of 0.05. Williams et al. (1999) obtained 3 multipoint MLSs greater than 1.5, and on this basis they considered the results on chromosomes 4p, 18q, and Xcen as suggestive. However, none approached a genomewide significance of 0.05. The power of this study was greater than 0.95 to detect a susceptibility locus with a susceptibility value (the relative risk to sibs resulting from possession of the disease allele) of 3, but only 0.70 to detect a locus with a susceptibility value of 2. Williams et al. (1999) interpreted their results as suggesting that common genes of major effect (susceptibility ratio more than 3) are unlikely to exist for schizophrenia.
Ekelund et al. (2000) conducted a 4-stage genomewide scan in a Finnish schizophrenia study sample consisting of 134 affected sib pairs. A lod score of 3.18 was obtained with marker D7S486 using a dominant model and treating all individuals with schizophrenia, schizoaffective disorder, or other schizophrenia spectrum disorder as affected. A multipoint lod score of 3.53 was generated between markers D7S501 and D7S523 using the broadest diagnostic model, including major depressive disorder and bipolar type I as affecteds in addition to the aforementioned phenotypes. Some support was also obtained for linkage to chromosome 1, in a region previously identified in a genomewide scan of a study sample from a subisolate of Finland.
Gurling et al. (2001) performed genetic linkage analysis in 13 large families in which multiple members in 3 or more generations suffered from schizophrenia. Other selection characteristics were absence of bipolar affective disorder and a single progenitor source of schizophrenia with unilineal transmission into the branch of the kindred sample. They found lod scores greater than 3.0 at 5 distinct loci, either in the sample as a whole or within single families, strongly suggesting etiologic heterogeneity. Heterogeneity lod scores greater than 3.0 in the sample as a whole were found at 1q33.2, 5q33.2, 8p22.1-p22, and 11q21. Lod scores greater than 3.0 within single pedigrees were found at 4q13-q31 and at 11q23.3-q24. A lod score of 2.9 was also found at 20q11.23-q12.1 within a single family. Other studies had previously detected lod scores greater than 3.0 at 4 of these sites: 1q33.2, 5q33.2, 8p22-p21, and 11q21. Gurling et al. (2001) concluded that the weight of evidence for linkage to 1q22, 5q33.2, and 8p22-p21 is sufficient to justify intensive investigation of these areas by methods based on linkage disequilibrium.
Paunio et al. (2001) conducted a third genomewide scan in a nationwide Finnish schizophrenia study sample of 238 pedigrees with 591 affected individuals. Of the 238 pedigrees, 53 originated from a small internal isolate on the eastern border of Finland. In addition to the previously identified chromosome 1 locus, 2 new loci were identified in the cohort on chromosomes 2q and 5q (see SCZD1). The highest lod scores were found in the internal isolate families with marker D2S427 (maximum lod = 4.43) and in the families originating from the late settlement region with marker D5S414 (maximum lod = 3.56).
To assess evidence for genetic linkage of schizophrenia across studies, Lewis et al. (2003) applied the rank-based GSMA method (Levinson et al., 2003) to data from 20 schizophrenia genome scans. The GSMA produced significant genomewide evidence for linkage on 2q. Two aggregate criteria for linkage were also met for several chromosomal regions. There was greater consistency of linkage results across studies than had previously been recognized. Lewis et al. (2003) suggested that some or all of these regions contained loci that increase susceptibility to schizophrenia in diverse populations.
Palauans are an isolated population in Micronesia with lifetime prevalence of schizophrenia of 2%, compared to the world rate of approximately 1%. The possible enrichment for SCZD genes, in conjunction with the potential for reduced etiologic heterogeneity and the opportunity to ascertain statistically powerful extended pedigrees, made Palauans a population of choice for the mapping of SCZD genes. Camp et al. (2001) used a Markov-chain Monte Carlo method to perform a genomewide multipoint analysis in 7 extended pedigrees from Palau. Four regions of interest were identified. Two of these (on chromosomes 2p14-p13 and 13q12-q22) had evidence for linkage with genomewide significance, after correction for multiple testing. A third region, with intermediate evidence for linkage, was identified on 5q22-qter. The fourth region of interest (on 3q24-q28) had only borderline suggestive evidence for linkage. All regions exhibited evidence for genetic heterogeneity.
Klei et al. (2005) performed linkage analysis on all 150 known schizophrenia patients and 25 individuals with other psychotic disorders on the island of Palau. With both narrow and broad diagnostic schemes, the best evidence for linkage by 2-point analysis was found for 3q28 (lod = 3.08) and 17q32.2 (lod = 2.80). Results from individual pedigrees supported linkage at 2q37.2, 2p14, and 17p13.
Williams et al. (2003) performed a systematic genomewide linkage study in 353 affected sib pairs with schizophrenia, using 372 microsatellite markers at approximately 10-cM intervals. The strongest finding was a lod score of 3.87 at chromosome 10q25.3-q26.3, with positive results being from each of 3 separate samples from the United Kingdom, Sweden, and the United States. They also found 2 regions, 17p11.2-q25.1 and 22q11, in which the evidence for linkage was highly suggestive. Linkage to all of these regions had been supported by other studies. In a single pedigree, furthermore, they found strong evidence for linkage to 17p11.2-q25.1. Williams et al. (2003) expressed the view that the evidence is now sufficiently compelling to undertake detailed mapping studies of these 3 regions.
O'Donovan et al. (2003) reviewed linkage studies and candidate genes in schizophrenia.
Maziade et al. (2005) performed a dense genome scan to identify susceptibility loci shared by schizophrenia and bipolar disorder. They used the same ascertainment, statistical, and molecular methods for 480 members from 21 multigenerational families from Eastern Quebec affected by schizophrenia, bipolar affective disorder, or both. Five genomewide significant linkages with maximized lod scores over 4.0 were observed: 3 for bipolar disorder (15q11.1, 16p12.3, 18q12-q21) and 2 for the shared 'common locus' phenotype (15q26, 18q12-q21). Nine maximized lod scores exceeded the suggestive threshold of 2.6: 3 for bipolar disorder (3q21, 10p13, 12q23), 3 for schizophrenia (6p22, 13q13, 18q21), and 3 for the combined locus phenotype (2q12.3, 13q14, 16p13). Maziade et al. (2005) noted that all of the linkage signals overlapped formerly reported susceptibility regions except the signal at 15q26.
Faraone et al. (2005) reported the results from a genome scan of 166 schizophrenia families collected through the U.S. Department of Veterans Affairs Cooperative Studies Program. Probands had either schizophrenia or schizoaffective disorder, depressed type, and families were defined as either European American or African American. Evidence for racial heterogeneity in the regions most suggestive for linkage was assessed. The maximum lod score across the genome was 2.96 for chromosome 18 at 0.5 cM in the combined race sample. Both racial groups showed lod scores greater than 1.0 for chromosome 18. The second and third largest linkage signals were solely from the African American sample and were found on chromosome 6 (lod = 2.11 at 33.2 cM) and chromosome 14 (lod = 2.13 at 50.1 cM).
Hamshere et al. (2006) performed a genomewide linkage analysis with the inclusion of lifetime presence/absence of depression as a covariate in a study of 168 sib pairs with schizophrenia in the U.K. They identified a significant linkage signal on chromosome 4q28.3 at 130.7 cM (lod = 4.59; p = 0.038) and suggestive evidence of linkage on chromosome 20q11.21.
In a large population-based study to identify gene copy number variations associated with schizophrenia, Stefansson et al. (2008) identified 26 of 4,718 patients with schizophrenia-related psychoses (0.55%) with a 470-kb 15q11.2 deletion, compared with 79 of 41,194 controls (0.19%). The deletion spanned approximately 470 kb, and several genes were deleted. The region is not imprinted.
Stefansson et al. (2009) combined SNP data from several large genomewide scans and followed up the most significant association signals. They found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p22.1-p21.3, a marker located upstream of the neurogranin gene (NRGN; 602350) on 11q24.2, and a marker in intron 4 of transcription factor-4 (TCF4; 602272) on 18q21.2. Stefansson et al. (2009) concluded that their findings implicating the MHC region (see SCZD3, 600511) are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 point to perturbation of pathways involved in brain development, memory, and cognition. The T allele of the SNP rs6932590 in the MHC region achieved a P value of 1.4 x 10(-12). For the NRGN association, mapped by the T allele of rs12807809, the P value was 2.4 x 10(-9), and for TCF4, mapped by the C allele of rs9960767, the P value was 4.1 x 10(-9).
The Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) reported a multistage schizophrenia genomewide association study of up to 36,989 cases and 113,075 controls. They identified 128 independent associations spanning 108 conservatively defined loci that met genomewide significance, 83 of which had not been previously reported. Associations were enriched among genes expressed in brain, providing biologic plausibility for the findings. Many of these findings could provide insights into etiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlighted molecules of known and potential therapeutic relevance to schizophrenia, and were consistent with leading pathophysiologic hypotheses. Independently of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. To further explore the regulatory nature of the schizophrenia associations, the Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) mapped the 108 credible sets of causal variants onto sequences with epigenetic markers characteristic of active enhancers in 56 different tissues and cell lines. Schizophrenia associations were significantly enriched at enhancers active in brain but not in tissues unlikely to be relevant to schizophrenia (for example, bone, cartilage, kidney, and fibroblasts). Brain tissues used to define enhancers consisted of heterogeneous populations of cells. Seeking greater specificity, the Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) contrasted genes enriched for expression in neurons and glia using mouse ribotagged lines. Genes with strong expression in multiple cortical and striatal neuronal lineages were enriched for associations, providing support for an important neuronal pathology in schizophrenia. These associations were also strongly enriched at enhancers that are active in tissues with important immune functions, particularly B-lymphocyte lineages involved in acquired immunity (CD19, 107265 and CD20, 112210). These enrichments remained significant even after excluding the extended MHC region and the regions containing brain enhancers (enrichment p for CD20 is less than 10(-6)), demonstrating that this finding is not an artifact of correlation between enhancer elements in different tissues and is not driven by the strong and diffuse association at the extended MHC.
Association with Deletion at Chromosome 1q21.1
In a large population-based study to identify gene copy number variations associated with schizophrenia, Stefansson et al. (2008) found that in 11 of 4,718 cases tested (0.23%), a microdeletion at chromosome 1q21.1 was present, compared to 8 of the 41,199 controls tested (0.02%). In 7 of the 11 patients, the deletion spanned about 1.35 Mb. See also de Vries et al. (2005), Sharp et al. (2006), Weiss et al. (2008), and Walsh et al. (2008). Four cases had a larger form of the deletion, which contained the shorter form and spanned about 2.19 Mb. The short form of the 1q21.1 deletion had been reported in mental retardation (de Vries et al., 2005; Sharp et al., 2006), autism (Weiss et al., 2008), and schizophrenia (Walsh et al., 2008).
In a genomewide survey of rare copy number variations in schizophrenia, the International Schizophrenia Consortium (2008) identified 10 patients with a chromosome 1 (142.5-145.5 Mb) deletion among 3,391 patients and 1 among 3,181 ancestrally-matched controls (empirical P = 0.0076; genomewide corrected P = 0.046; odds ratio 6.6). Among the 10 deletion cases on chromosome 1q21.1, 3 had mild cognitive abnormalities and 1 had a history of epilepsy. The region contains 27 known genes expressed in the brain. The authors also cited the studies of Sharp et al. (2006), Weiss et al. (2008), and Walsh et al. (2008) relative to this deletion.
To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of deletion in chromosome 1q21 with autism and schizophrenia (CNV P = 1.67 x 10(-4)). They identified 27 CNVs in this region; 24 of these were disease-associated.
Association with Duplication at Chromosome 7q36.3
For discussion of an association between schizophrenia and duplication at chromosome 7q36.3, see (613959).
Association with Duplication at Chromosome 15q11-q13
For discussion of an association between schizophrenia and copy number variations at chromosome 15q11-q13, see 613025.
Association with Deletion at Chromosome 17q12
Moreno-De-Luca et al. (2010) performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders and detected a recurrent 1.4-Mb deletion at chromosome 17q12 (see 614527) in 18 of 15,749 patients, including 6 with autism or autistic features (see 209850); the deletion was not found in 4,519 controls. In a large follow-up sample, the same deletion was identified in 2 of 1,182 patients with autism spectrum disorder and/or neurocognitive impairment, and in 4 of 6,340 schizophrenia patients, but was not found in 47,929 controls (corrected p = 7.37 x 10 (-5)). Moreno-De-Luca et al. (2010) concluded that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for autism spectrum disorder and schizophrenia, and that 1 or more of the 15 genes in the deleted interval is dosage-sensitive and essential for normal brain development and function.
Association with Deletion at Chromosome 22q11
Liu et al. (2002) reviewed the association of schizophrenia with microdeletions of chromosome 22q11, which are approximately 100 times more frequent in adult schizophrenic patients than in the general population and occur in up to 6% of childhood-onset schizophrenia cases. The magnitude of the risk attributed to this deletion is unprecedented in schizophrenia for a single genetic lesion and is comparable only to the risk among children of 2 schizophrenic parents or monozygotic cotwins of an affected individual. In both of these cases, the increased risk is due to the contribution of more than 1 susceptibility gene. It is therefore possible that the increased risk associated with microdeletions of 22q11 is due to the contribution of more than 1 physically linked gene at this locus. Liu et al. (2002) performed linkage disequilibrium studies in family samples (trios) that tested for preferential transmission of common variants and multivariant haplotypes from parents to affected individuals. The studies were based on (and therefore tested) the assumptions that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to approximately 2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers in the vicinity of the 22q11 locus in both family- and population-based samples, Liu et al. (2002) presented results consistent with this assumption. Finer-scale haplotype mapping identified 2 subregions within the 1.5-Mb locus that were thought to harbor candidate schizophrenia susceptibility genes.
In a genomewide survey of rare copy number variations in schizophrenia, the International Schizophrenia Consortium (2008) identified 13 large deletions (more than 500 kb) in the 22q11.2 deletion interval associated with velocardiofacial syndrome (192430) and DiGeorge syndrome (188400) in 3,391 cases of schizophrenia and none in 3,181 controls. The 11 samples consistent with the typical deletions defined an interval with the strongest association (empirical P = 0.0017; genomewide corrected P = 0.0046; odds ratio 21.6). The authors noted that approximately 30% of patients with 22q11.2 deletion-associated phenotypes develop psychosis.
To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of deletion at chromosome 22q11 with autism, mental retardation, and schizophrenia (CNV p = 7.93 x 10(-9)). They identified 31 CNVs in this region; all of these were disease-associated.
Association with Other Microdeletions and Copy Number Variations
Walsh et al. (2008) hypothesized that individually rare structural variants contribute to schizophrenia. Microdeletions and microduplications greater than 100 kb were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin (see 142445) and glutamate pathways. Walsh et al. (2008) concluded that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
In a comment on the paper of Walsh et al. (2008) demonstrating an elevated frequency of gene structural variants in patients with schizophrenia, Leonard and Kuldau (2008) noted that 'Buried within the Supporting Online Material is the astonishing fact that 47% of the patients with poor cognitive function (IQ less than 80) had these variants, compared with only 11% of the patients with normal IQ.' Leonard and Kuldau (2008) proposed that perhaps genomic deletions and duplications have an unspecific effect restricting the flexibility of coping responses during development, constraining neuroplasticity, and rendering cognitive function more dependent on intrinsic neurobiology. McClellan et al. (2008) responded that while they agreed that the association between cognitive delays and rare structural mutations in their sample was striking, the sample size was very small. Of 15 schizophrenic patients with cognitive delay, 6 carried chromosomal deletions or duplications. McClellan et al. (2008) also stressed that structural mutations can have a remarkably variable effect among individuals who carry them, and cited the variation in the Scottish pedigree harboring the DISC1 translocation reported by Chubb et al. (2008).
Xu et al. (2008) examined the possibility that rare de novo copy number mutations with relatively high penetrance contribute to the genetic component of schizophrenia. They carried out a whole-genome scan using the Affymetrix 5.0 SNP array, which contains over 500,000 SNPs, and implemented a number of steps for finding and confirming copy number mutations. Confirmed de novo copy number changes were significantly associated with schizophrenia (p = 0.00078) and were collectively about 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited copy number mutations were only modestly enriched in sporadic cases. Xu et al. (2008) suggested that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.
Kirov et al. (2009) investigated the involvement of rare (less than 1%) copy number variants (CNVs) in 471 patients with schizophrenia and 2,792 controls who had been genotyped using a large microarray. Large CNVs (greater than 1 Mb) were 2.26 times more common in patients (p = 0.00027), with the effect coming mostly from deletions (odds ratio = 4.53, p = 0.00013). Two large deletions were found in 2 patients each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia, and a deletion on 17p12, at 14.0-15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies (HNPP; 162500). The same deletion was found in 6 of 4,618 (0.13%) patients and 6 of 36,092 (0.017%) controls in the reanalyzed data of 2 large CNV studies of schizophrenia (OR = 7.82, p = 0.001), with the combined significance level for all 3 studies achieving p = 5 x 10(-5). One large duplication on 16p13.1, which had previously been implicated as a susceptibility factor for autism, was found in 3 patients and 6 controls (0.6% vs 0.2%, OR = 2.98, p = 0.13).
Mulle et al. (2010) reported the results of a genomewide association study for CNVs among 245 unrelated patients with SCZD and 490 controls, all of Ashkenazi Jewish descent. One of the identified candidate regions was on chromosome 3q29. Combined with prior CNV studies and additional SCZD cohorts, the authors identified 3q29 deletions in 6 of 7,545 patients compared to 1 in 39,748 controls (odds ratio of 16.98; corrected p value = 0.02). The minimum deletion region overlapped with that observed in a group of children with moderate mental retardation and autism (609425) and included 20 annotated genes.
Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (610543, 613458), and 22q11.2 (192430, 608363). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions.
Association with Eye Tracking Dysfunction
In a study of 89 individuals from 10 large families with multiple occurrence of schizophrenia (2 or more cases), Arolt et al. (1999) found significant linkage of eye tracking dysfunction (ETD), a putative phenotypic biologic marker of schizophrenia, to markers D6S271 (maximum lod = 3.70) and D6S282 (maximum lod = 2.85) on chromosome 6p23-p21, as well as indication of possible linkage for schizophrenia. Using the 'latent trait' model for the cotransmission of schizophrenia and ETD in a study of 2 large families in Denmark, Matthysse et al. (2004) found a lod score of 2.05 for D6S1017, a marker within 3 cM of the positive markers obtained by Arolt et al. (1996, 1999).
Association with Cognitive Traits
Paunio et al. (2004) analyzed genomewide data for 168 Finnish schizophrenia families using neuropsychologic variables associated with disease susceptibility. The linkage signal was greatly accentuated by application of the quantitative traits compared with diagnosis. A locus for verbal learning and delayed memory was found on 4q21 (lod = 2.96 and 3.01, respectively), and there was suggestive evidence for a visual working memory locus on 2q36 (lod = 2.80). Some evidence emerged for a locus for recognition memory on 10p13, visual attention on 15q22, and executive function on 9p22 in the complete sample, as well as for delayed memory on 8q12, semantic clustering, and intrusions on 1q42 and visual attention on 3p25 in a genealogically distinct subset.
Association with Relative Hand Skill
Schizophrenia and relative hand skill (HSR; 139900) are moderately associated, and both traits are often accompanied by abnormalities of asymmetrical brain morphology or function. Francks et al. (2003) found that in a sample of 191 reading-disabled sib pairs, the relative hand skill of sibs was correlated more strongly with paternal than maternal relative hand skill (p = 0.0000037 for paternal identity-by-descent sharing). Similarly, in affected sib-pair analysis of 241 schizophrenic sib pairs, the authors found linkage to schizophrenia for paternal sharing (lod = 4.72; p = 0.0000016) within 3 cM of the peak linkage to relative hand skill. Francks et al. (2003) suggested that the causative genetic effects on chromosome 2p12-q11 may be related, and they proposed that these linkages may be due to a single maternally imprinted influence on lateralized brain development that contains common functional polymorphisms.
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%, 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 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 rs348624 (which was in complete LD with 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 rs1415263 and the C allele of 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 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 (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.
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 (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 ZNF804A gene on Chromosome 2q31
O'Donovan et al. (2008) found evidence for an association of schizophrenia with a T allele at SNP 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 rs2307981, rs2308169, rs308963, rs795009, and 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; 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 600511.
Association with the NOTCH4 Gene on Chromosome 6p21
See 600511.
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 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 (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.
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 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.
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 SETD1A gene on Chromosome 16p11.
For discussion of a possible association between schizophrenia susceptibility and variation in the SETD1A gene, see 611052.
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 (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
See 182138 for discussion of a possible association of schizophrenia susceptibility with the SLC6A4 gene on chromosome 17q11.
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 C4A and C4B Genes on Chromosome 6p21.3
Kamitaki et al. (2020) noted that systemic lupus erythematosus (SLE; 152700) and Sjogren syndrome (see 270150) affect 9 times more women than men, whereas schizophrenia affects men with greater frequency and severity than women. Kamitaki et al. (2020) showed that variation in the C4A (120810) and C4B (120820) genes, which are located in the major histocompatibility complex (MHC) locus, generated 7-fold variation in risk for SLE and 16-fold variation in risk for Sjogren syndrome among individuals with common C4 genotypes, with C4A offering stronger protection than C4B in both illnesses. C4 alleles that increased risk for schizophrenia greatly reduced risk for SLE and Sjogren syndrome. In all 3 illnesses, C4 alleles acted more strongly in men than in women, with common combinations of C4A and C4B generating 14-fold variation in risk for SLE, 31-fold variation in risk for Sjogren syndrome, and 1.7-fold variation in schizophrenia risk among men versus 6-fold, 15-fold, and 1.26-fold variation in risk among women, respectively. Protein levels of both C4 and its effector C3 (120700) were higher in cerebrospinal fluid and plasma in men compared with women among adults between 20 and 50 years of age, corresponding to the ages of differential disease vulnerability. Kamitaki et al. (2020) concluded that sex differences in complement protein levels may explain the more potent effects of C4 alleles in men, the greater risk in women of SLE and Sjogren syndrome, and the greater vulnerability in men to 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 rs1059004 and 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 (rs175174) in intron 4 of the ZDHHC8 gene (608784), had the strongest association of all 72 SNPs tested. Mukai et al. (2004) showed that 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 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 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 or TOP3B 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.
Xu et al. (2012) sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios, and observed in cases an excess of de novo nonsynonymous single-nucleotide polymorphisms (SNPs) as well as a higher prevalence of gene-disruptive de novo mutations relative to controls. Two genes within the 22q11.2 schizophrenia susceptibility locus, DGCR2 (600594) and TOP3B (603582), were altered by both a de novo SNP and a de novo copy number variation (deletion in both cases) in an Afrikaner cohort, one of 2 populations studied.
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.
Exclusion Studies
In a case-control association study of 42 Caucasian patients with schizophrenia and 47 unaffected controls matched for ethnicity, Nimgaonkar et al. (1995) found no evidence for an association between schizophrenia and the IL2RB (146710) locus on chromosome 22q12.
Using 2-point followed by multipoint lod and nonparametric linkage analyses under the assumption of heterogeneity in 23 schizophrenia pedigrees drawn from Iceland and the UK, Kalsi et al. (1995) found no evidence for linkage to markers D22S274 and D22S283, which span the 22q12-q13 region.
In an effort to circumvent the problems encountered by previous studies in ethnically diverse populations, Riley et al. (1996) tested for linkage between highly polymorphic chromosome 22 markers and schizophrenia in a sample of South African Bantu-speaking black families, a population known to have diverged within the last 2,000 years. They found no evidence to support a schizophrenia susceptibility locus on chromosome 22 in this population when they used either parametric or nonparametric analyses. Using several different models of transmission in an analysis of 23 schizophrenia families, Parsian et al. (1997) found no evidence for a schizophrenia susceptibility locus on 22q.
Mowry et al. (2004) evaluated 10 microsatellite markers spanning chromosome 22q in a multicenter sample of 779 pedigrees. The study also incorporated age at onset and gender into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. Mowry et al. (2004) concluded that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis, even in large samples.
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.
Formal genetic modeling suggests that environmental factors do not contribute significantly to the pathogenesis of schizophrenia (McGuffin et al., 1994). However, there is evidence for a role of environmental factors in the etiology of at least some forms of schizophrenia. Exposure to certain drugs results in similar syndromes, classified separately by DSM-IV. Numerous studies have demonstrated a 5 to 8% excess of schizophrenia births in the winter-spring months, both in the Northern and Southern hemispheres, particularly for those with a negative family history (Torrey et al., 1997). Seasonal correlates and birth date may be the result of certain infections, perinatal brain damage which may vary as do stillbirths and prematurity with the season, or nutritional deficiencies. Tam and Sewell (1995) collected data on 3,346 Taiwanese patients diagnosed with schizophrenia, demonstrating an excess of births in the cold months compared to the hot months in agreement with the findings in previous studies with European and North American populations. Further evidence suggesting the action of environmental factors in at least some forms of schizophrenia comes from associations with latitude, urban birth, household crowding, having older sibs, and famine during pregnancy (Yolken and Torrey, 1995).
Davis and Phelps (1995) reanalyzed data on handedness from 3 recent studies on samples of twins in whom one or both had schizophrenia and found that monozygotic twin pairs with opposite hand preferences were concordant for psychosis in 60% of cases, whereas only 32% of same hand preference monozygotic twins were concordant for psychosis. They speculated that opposite-hand preferences in these monozygotic twins were the result of late twinning and subsequent sharing of a single placenta. They speculated further that monochorionic monozygotic twins, who would be more susceptible to shared prenatal infections, are more concordant for schizophrenia than are dichorionic monozygotic twins.
The symptoms of schizophrenia appear to be associated with functional and structural changes in a number of neocortical regions, including heteromodal prefrontal and temporal-association cortices, as well as in the connections and integrative interactions among these regions, corticolimbic areas, and the thalamus. Although some genetic abnormalities may contribute to the cause of schizophrenia, their poor penetrance suggests that this disorder is not exclusively related to either single- or multiple-gene defects. The absence of obvious early psychopathology in children who are diagnosed with schizophrenia later in life suggests that schizophrenia may involve a '2-hit' process. Genetic load, adverse embryonic events, and perinatal events may be considered a neurodevelopmental first hit that leads to vulnerability to schizophrenia. The most frequently cited embryonic and perinatal factors include viral illness during the second trimester of pregnancy, low birth weight, short gestational period, and perinatal brain damage. Hormonal events, such as altered neurosteroid biosynthesis, during puberty acting per se or presumably integrating with the residues of developmentally related changes could act as a second hit, facilitating excitotoxicity or oxygen radical formation due to environmental factors (summary by Impagnatiello et al., 1998).
By use of microarray expression profiling of prefrontal cortex from matched pairs of patients with schizophrenia and control subjects and hierarchical data analysis, Mirnics et al. (2000) found that transcripts encoding proteins involved in the regulation of presynaptic function were decreased in all subjects with schizophrenia. Genes of presynaptic function showed a different combination of decreased expression across subjects. Over 250 other gene groups did not show altered expression. Selected presynaptic function gene microarray observations were verified by in situ hybridization. Two of the most consistently changed transcripts in the presynaptic functional gene group, N-ethylmaleimide-sensitive factor (601633) and synapsin-2 (600755), were decreased in 10 of 10 and 9 of 10 subjects with schizophrenia, respectively. The combined data suggested that subjects with schizophrenia share a common abnormality in presynaptic function.
Mimmack et al. (2002) screened a custom-made cDNA array comprising 300 candidate schizophrenia genes using probes derived from prefrontal cortex tissue of 10 schizophrenia and 10 control brains. The screen revealed a 2.6-fold upregulation of apolipoprotein L1 (APOL1; 603743), and this finding was confirmed in prefrontal cortex tissue from the brain collection of the Stanley Foundation and in 20 schizophrenia and 20 control brains from Japan and New Zealand. Mimmack et al. (2002) also found that APOL2 (607252) and APOL4 (607254) were significantly upregulated in schizophrenia. The APOL proteins belong to a group of high density lipoproteins, and all 6 APOL genes are located in close proximity to each other on chromosome 22q12, a confirmed high-susceptibility locus for schizophrenia (SCZD4) and close to the region associated with velocardiofacial syndrome, which includes symptoms of schizophrenia. The high density lipoprotein family plays a central role in cholesterol transport. The cholesterol content of membranes is important in cellular processes such as modulating gene transcription and signal transduction both in the adult brain and during neurodevelopment.
Cannon et al. (2002) performed radiologic studies of cortical gray matter deficits in monozygotic (MZ) and dizygotic (DZ) twins discordant for chronic schizophrenia along with demographically matched control twins. A map encoding the average differences between schizophrenia patients and their unaffected MZ cotwins revealed deficits primarily in dorsolateral prefrontal cortex, superior temporal gyrus, and superior parietal lobule. The disease-related deficits in gray matter were correlated with measures of symptom severity and cognitive dysfunction but not with duration of illness or antipsychotic drug treatment.
Emamian et al. (2004) presented their convergent evidence for an important role of the AKT1 (164730)/GSK3B (605004) signaling pathway in schizophrenia. This signaling pathway was already recognized as a target of lithium, which is used for the treatment of mood disorders. They presented convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3B at ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia as well as other supporting evidence, identifying AKT1 as a potential schizophrenia susceptibility gene. AKT1 was first cloned as the cellular homolog of the v-act oncogene and is also known as protein kinase B. It is a multifunctional protein kinase, linked to several signaling pathways mediating multiple responses and may be regulated by a large number of protein-protein interactions (Hallmayer, 2004).
Dean et al. (2002) tested the hypothesis that muscarinic receptors are involved in the pathophysiology of schizophrenia by measuring muscarinic-1 (CHRM1; 118510) and muscarinic-4 (CHRM4; 118495) protein and mRNA as well as [3H]pirenzepine binding in Brodmann's area (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. They observed a significant decrease in [3H]pirenzepine binding to BA 9 (p less than 0.02) but not BA 40 from subjects with schizophrenia. The level of CHRM1 protein (p less than 0.01) but not CHRM4 protein was decreased in BA9 from schizophrenic subjects but neither protein was altered in BA40. The level of CHRM1 mRNA was decreased in BA 9 (p less than 0.01) and BA 40 (p less than 0.01) with schizophrenia, but CHRM4 mRNA was only decreased in BA 40 (p less than 0.005). Dean et al. (2002) interpreted the data as indicating that CHRM1 changes in the dorsolateral prefrontal cortex may have a role in the pathology of schizophrenia.
Perkins et al. (2005) noted that nonprotein coding RNA (ncRNA) plays a critical role in regulating the timing and rate of protein translation. They discussed the possibility that ncRNA regulation of genes may account for the diverse findings of genetic linkage and association studies for schizophrenia, including findings that altered gene polymorphisms are not generally found in schizophrenia. They suggested that inadequate or mistimed expression of a functional protein may result from a mutation or other dysfunction of the encoding DNA that leads to a dysfunctional protein, or from posttranscriptional events such as abnormal ncRNA regulation of a normal gene.
Millar et al. (2005) reported that the gene encoding phosphodiesterase 4B (PDE4B; 600127) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The phosphodiesterases inactivate cAMP, a second messenger implicated in learning, memory, and mood. They showed that DISC1 (605210) interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and in increase in PDE4B activity. Millar et al. (2005) proposed a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
Hahn et al. (2006) found that postmortem tissue slices of prefrontal cortex obtained from patients with schizophrenia demonstrated significantly increased NRG1-induced activation of ERBB4 (600543) compared to controls despite similar levels of the 2 proteins. NRG1-induced suppression of NMDA receptor (see, e.g., GRIN1; 138249) activation was more pronounced in schizophrenia subjects compared to controls, consistent with enhanced NRG1-ERBB4 signaling. The findings were consistent with the hypothesis that NMDA receptor hypofunction may play a role in schizophrenia. An Editorial Expression of Concern has been published regarding the Western blot images presented in some of the figures in the article by Hahn et al. (2006).
Because risk of schizophrenia is associated with prenatal/obstetric complications, including preeclampsia and low birth weight, and because maternal-fetal HLA matching has been associated with these complications and with at least 1 other neurodevelopmental disorder, namely, autism (see 209850) (Stubbs et al., 1985), Palmer et al. (2006) hypothesized that maternal-fetal HLA matching may be a risk factor of schizophrenia. A statistically significant HLA-B (142830) genotype-matching effect on schizophrenia was demonstrated for female offspring (P = 0.01). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease.
Toyota et al. (2004) stated that the increased incidence of minor physical anomalies in schizophrenia is the fundamental basis for the neurodevelopmental hypothesis of schizophrenia etiology. See review of McNeil et al. (2000).
Brennand et al. (2011) directly reprogrammed fibroblasts from schizophrenia patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons. SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95 (602887) protein levels, and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cAMP and WNT (see 606359) signaling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine.
To study genomewide mutation rates, Kong et al. (2012) sequenced the entire genomes of 78 Icelandic parent-offspring trios at high coverage. Forty-four of the probands had autistic spectrum disorder and 21 were schizophrenic. Kong et al. (2012) found that, with an average father's age of 29.7, the average de novo mutation rate is 1.20 x 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single-nucleotide polymorphisms was dominated by the age of the father at conception of the child. The effect is an increase of about 2 mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. Kong et al. (2012) stated that there had been a recent transition of Icelanders from a rural agricultural to an urban industrial way of life, which engendered a rapid and sequential drop in the average age of fathers at conception from 34.9 years in 1900 to 27.9 years in 1980, followed by an equally swift climb back to 33.0 years in 2011, primarily owing to the effect of higher education and the increased use of contraception. On the basis of the fitted linear model, whereas individuals born in 1900 carried on average 73.7 de novo mutations, those born in 1980 carried on average only 59.7 such mutations (a decrease of 19.1%), and the mutational load of individuals born in 2011 had increased by 17.2% to 69.9. Kong et al. (2012) concluded that their observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.
Fromer et al. (2014) reported the largest exome sequencing study of de novo mutations in schizophrenia to that time, using genomic DNA from 623 schizophrenia trios. Fromer et al. (2014) showed that small de novo mutations, affecting 1 or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC; 612461) and NMDA receptor (see GRIN1, 138249) complexes. Mutations were additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely, proteins regulating actin filament dynamics and those whose mRNAs are targets of fragile X mental retardation protein (FMRP; 309550). Genes affected by mutations in schizophrenia overlap those mutated in autism (see 209850) and intellectual disability, as do mutation-enriched synaptic pathways. Fromer et al. (2014) aligned their findings with a parallel case-control study, which demonstrated reproducible insights into etiologic mechanisms for schizophrenia and revealed pathophysiology shared with other neurodevelopmental disorders.
Purcell et al. (2014) analyzed the exome sequences of 2,536 schizophrenia cases and 2,543 controls and demonstrated a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets included the voltage-gated calcium ion channel (see 602911) and the signaling complex formed by the scaffold protein ARC of the postsynaptic density, sets previously implicated by genomewide association and copy number variation studies. Similar to reports in autism, targets of FMRP are enriched for case mutations. No individual gene-based test achieved significance after correction for multiple testing, and Purcell et al. (2014) did not detect any alleles of moderately low frequency (approximately 0.5 to 1%) and moderately large effect. Purcell et al. (2014) concluded that, taken together, their data suggested that population-based exome-sequencing can discover risk alleles and complemented established gene-mapping paradigms in neuropsychiatric disease.
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