Schizophrenia
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.
DescriptionSchizophrenia 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.
NomenclatureIn 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.
Clinical FeaturesSchizophrenia 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.
Other FeaturesVawter 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.
InheritanceSchizophrenia 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.
DiagnosisThe 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.
Clinical ManagementSchizophrenia 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.
Population GeneticsIf 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).
CytogeneticsChodirker 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.
MappingLinkage 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