242 Taiwanese J Psychiatry Vol. 21 No. 4 2007

Chromosomal Abnormalities and Discovery in Schizophrenia

Jye-Siung Fang, Ph.D.1, Chia-Hsiang Chen, M.D., Ph.D.1,2,3,4

Background: Schizophrenia is a complex disease in its clinical aspect, it is also complex in genetic aspect. Hence, schizophrenia can be considered a complex genetic disease. Currently, there are several approaches to investigate the genetic underpinnings of schizophrenia, such as genetic linkage analysis, genome-wide as- sociation study, analysis, and genomic study. Lilerature Reviews: The results from these studies show that schizophrenia can be associated with com- mon variants of many , and each gene contributes a small to modest risk to schizophrenia. In addition, schizophrenia can also be associated with rare muta- tions in a single gene that plays an essential role in brain function. Schizophrenia patients with chromosomal abnormalities belong to this category. The incidence of chromosomal abnormalities in the schizophrenic population is rare, and psychiat- rists rarely refer schizophrenia patients for cytogenetic examinations. However, with the progress of molecular genetic technology, the new molecular cytogenetics becomes an important tool to discover genes-associated with schizophrenia. Chro- mosomal rearrangement is a common biological phenomenon in , which can lead to inversion, translocation, deletion, and duplication of chromo- some segments. Some rearrangements can cause diseases including psychiatric di- sorders. The accurate localization of these regions can help identify the disease-as- sociated genes. Results: There are increasing reports of chromosomal aberrations associated with schizophrenia in the literature, and multiple schizophrenia genes have been identified through these chromosomal aberrations. Furthermore, the re- cent development of high density array comparative genome hybridization has gre- atly improved the resolution of conventional karyotype analysis, and studies have shown that this new technology is useful in detecting submicroscopic deletion and duplication in patients with developmental disorder and mental illness. Con- clusion: The combination of conventional karyotype examination and new mol- ecular cytogenetic analysis will offer an invaluable opportunity to discover genes associated with schizophrenia, leading to new insights into the pathogenesis of schizophrenia, and to better treatment of patients with schizophrenia in the future.

Key words: schizophrenia, chromosome, gene, pathogenesis (Taiwanese J Psychiatry 2007;21:242-53)

1Graduate Institute of Human Genetics, Tzu-Chi University, Hualien 2Department of Psychiatry, Tzu-Chi General Hospital, Hu- alien 3Department of Psychiatry, Tzu-Chi University, Hualien 4Division of Mental Health and Substance Abuse Research, Na- tional Health Research Institutes, Zhunan Address correspondence to: Dr Chia-Hsiang Chen, Department of Psychiatry, Tzu-Chi General Hospital and University, No. 707, Sec. 3, Chung-Yang Road, Hualien 970, Taiwan Fang JS, Chen CH 243

tal factors. The other one is the multiple rare vari- Introduction ant model; some patients may have rare mutations in single genes which are severe enough to cause It is generally accepted now that schizo- clinical symptoms of schizophrenia, while differ- phrenia is a complex disease with a high genetic ent patients have different mutations in the same component in its etiology. There are several differ- gene or mutation in different disease-causing ent meanings for "complexity"; it may represent genes [7]. These two models are not exclusive to varied expression in clinical presentation, i.e. cli- each other, they may co-exist in the schizophrenic nical heterogeneity; it may also represent different population, with some patients fitting the com- causes underlying the same clinical diagnosis, i.e. mon variant model, while some other patients fit- etiological heterogeneity and phenocopy [1, 2]. ting the rare mutation model. Depending on the Schizophrenia has a heritability estimate of ap- model, there are different approaches that can be proximately 80% on average, indicating that gene- adopted to search for the genetic underpinnings of tics plays a major role in its etiology, while non- schizophrenia; different methods face different genetic factors contribute a relatively small por- difficulties and problems. tion of the etiology of schizophrenia. From the For the common variant model of schizo- genetic aspect, schizophrenia can be considered a phrenia, population-based case-control associ- complex genetic disorder; it may have different ation design is the most popular approach, be- genetic underpinnings under the same diagnosis cause it can detect genetic variants with small to of schizophrenia, including locus heterogeneity modest effects on the susceptibility of schizo- (different disease-causing genes) and allelic het- phrenia [8]. Current high throughput technology erogeneity (same disease-causing gene but differ- allows simultaneous genotyping of five hundred ent mutations). It may also have varied clinical ex- thousand single nucleotide polymorphic DNA pression with the same genetic defects (pene- markers (500K SNPs) in each subject with a high trance and pleiotropism), or it may be caused by accuracy rate, which is a powerful tool for geno- intergenic interactions (epistasis), or gene-envi- me-wide association [9]. However, there are se- ronment interactions [3, 4]. Hence, it is difficult to veral factors that may influence the validity of the describe the whole picture of the genetic etiology results, such as consistency of clinical diagnosis, of schizophrenia in a simple way. sample size, and the cost [10]. In addition, there Currently there are two major genetic models are several other issues which need to be address- to explain the genetic etiology of common com- ed using this approach. First, there are inconsistent plex diseases [5], which can also apply to schizo- results in replicate studies in different populations, phrenia. One is the common variant model: even in the same population. Second, the SNPs schizophrenia is associated with common variants that show positive association with schizophrenia of multiple genes, with each gene contributing a are usually located at intronic regions; it is diffi- small to modest risk to the susceptibility of cult to test the functional significance of these in- schizophrenia [6]. The occurrence of schizo- tronic SNPs at the present time, not to mention phrenia is the combined effect of the interactions their clinical relevance. Third, the odds ratios ob- among these genes that cross the threshold of cli- tained from these studies are usually small, and it nical presentations, or is triggered by environmen- is difficult to test the neurobiological mechanism 244 Cytogenetics and Schizophrenia

of schizophrenia based on these findings. At the genetic studies in recent years. In this review, I present time, it is still difficult to apply positive will elucidate the important relationship of cyto- findings from case-control genetic association stu- genetic study and gene discovery in schizo- dies of schizophrenia to the clinical diagnosis and phrenia. treatment of schizophrenia. Classical genetic linkage analysis is a useful Chromosomal aberrations and schizo- method to locate the disease-causing gene locus in phrenia genetic diseases transmitted with known modes of inheritance; many genetic disease genes have Aneuploidy been identified using this method. However, it has only limited success in psychiatric diseases, which There are three categories of chromosome have complex modes of inheritance. To date, there abnormality, chromosome number change (aneu- is no schizophrenia gene identified by this meth- ploidy), fragile site expression, and chromosome od. The main reason is that it is inappropriate to rearrangement. There are only a few surveys ab- use a single gene mapping method to map genes of out chromosome abnormalities in schizophrenia complex disease like schizophrenia, in which the population; most reports about chromosomal ab- mode of inheritance is uncertain or heterogeneous normalities associated with schizophrenia are ane- [10,11]. To overcome this difficulty, a model-free cdotal case studies. In 1984, Axelsson and Wahl- gene mapping method, affected-sib pair linkage strom reported chromosome examinations in 134 analysis, has been undertaken to map complex men with psychotic disorders, they found sex disease genes. For example, Faraone et al. (2006) chromosome aberrations in 3 patients; one with employed this method in 557 families with af- 47, XXY, one with 47, XXY/46, XY, and one with fected sib-pairs from Taiwan and reported linkage 46, XY/45.XO [15]. In this study, the frequency of of schizophrenia to 10q22.3 [12]. The results ob- sex chromosome aberrations in this schizophrenia tained from genetic linkage analyses only show sample is significantly higher than that in new- possible susceptible gene loci for schizophrenia; borns, suggesting that sex may play more effort is needed to perform fine mapping and a role in the etiology of psychosis. In 1999, to pin down the schizophrenia genes. Kunugi and colleagues reported that in 250 Japa- Another important approach to identify the nese schizophrenic patients receiving cytogenetic genetic etiology of schizophrenia is the cytogen- examinations, 5 cases with aneuploidy of X chro- etic analysis of peripheral blood cells from pati- mosome and 10 cases with pericentric inversion of ents with schizophrenia. The incidence of chro- chromosome 9 were identified [16]. The incidence mosomal aberrations in schizophrenia population of these chromosomal aberrations in schizo- is rare, hence, clinical psychiatrists rarely refer phrenia is higher than in the general population in schizophrenic patients for cytogenetic examina- Japan. However, these results were not supported tions [13,14]. However, chromosomal aberrations by another research group from Japan. Toyota and associated with schizophrenia are very useful in colleagues repeated the studyandreportednoin- identifying the disease-causing genes and suscep- creased rates of X chromosome mosaicism or tible genes for schizophrenia. Several schizo- pericentric inversion of chromosome 9 in karyo- phrenia genes have been identified through cyto- type analysis of 161 unrelated schizophrenic pati- Fang JS, Chen CH 245

ents when compared to ethnically matched and 1q21 in 7 out of 19 unrelated schizophrenic pati- age-stratified controls [17]. They claimed that the ents [21]. Furthermore, Smith and colleagues re- discrepant results may result from the different ported that schizophrenic patients have significan- control subjects used in two studies. There is an tly more expression of fragile sites at chromosome increased rate of mosaicism of X chromosome 10q23 and 10q25 than that in controls [22]. Our aneuploidy with age, hence, they used age-match- group also performed a study on the fragile site ed control subjects rather than randomly selected expression in a sample of Chinese schizophrenic control subjects in their study. Prior and colle- patients from Taiwan. We found a significant ex- agues reviewed the literature and found that there cess of expression of fragile sites at chromosome is an approximately three-fold higher frequency of 2q11.2 and 9q12 in 72 schizophrenia patients as Turner syndrome in schizophrenic females than in compared to that in 66 controls [23]. In a more re- the general population, and the karyotypes of the cent study, Demirhan and colleagues reported that majority of these patients are mosaics of 46, there is a significantly higher frequency of fragile XX/45,XO [18]. However, the increased risk for site expression in Turkish patients with schizo- schizophrenia in persons with aneuploidy of sex phrenia than in the general Turkish population chromosome was not supported by a population- [24]. Taken together, these studies suggest fragile based study using the Danish Cytogeneitc Central site expression may be associated with schizo- Register and Danish Psychiatric Central Register phrenia. As abnormal expansion of CGG trinucleo- [19]. Hence, the association of X chromosome and tide repeats of FMR1 gene was found to be the schizophrenia remains unsettled. genetic mechanism of fragile X mental retarda- tion; abnormal expansion of trinucleotide repeats Fragilesiteexpression is considered a possible molecular basis of chro- Another important category of chromosome mosomal fragile site expression. Hence, genes studies for schizophrenia are association studies with trinucleotide repeats located at the fragile si- of fragile site expression in the schizophrenia tes and associated with schizophrenia are consid- population. Chromosomal fragile sites are break- ered good candidate genes for schizophrenia. age-prone regions that result from cells exposed to Chromosome rearrangement specific agents or tissue culture conditions. The association of the fragile site at Xq27.3 and mental Segmental rearrangement of chromosomes retardation is well-documented in literature. After can result in translocation, deletion, and duplica- the discovery that abnormal expansion of CGG re- tion of chromosomes, and some of these chromo- peats of the FMR1 gene is the genetic underpin- some rearrangements can cause diseases in hu- ning of fragile X mental retardation, there is an in- man. Interstitial deletion of chromosome 22q11 is creasing interest in studying fragile site ex- one of the most common chromosomal rearrange- pression in patients with schizophrenia. Garofalo ments in human, and results in the medical condi- and colleagues reported a significantly higher pre- tion of velocardiofacial syndrome (VCFS). VCFS sence of rare fragile sites at chromosome 9p21 and is characterized by conotruncal heart defects, cleft 10q21 in schizophrenic patients than that in con- palate and/or lip, and dysmorphic facial features. trols [20]. Fananas and colleagues reported an un- Of note is that patients with VCFS usually have expected spontaneous fragile site at chromosome symptoms such as cognitive impairment and psy- 246 Cytogenetics and Schizophrenia

chiatric disturbances, including mental retarda- Themostimpressiveexamplecomesfromthestu- tion, autism spectrum disorders, attention deficit dy of a Scottish family from Edinburgh with major disorder, mood disorders and schizophrenia spec- mental illness. In this multiplex family, cyto- trum disorder [25]. In addition, some patients with genetic analysis revealed a balanced translocation schizophrenia or childhood onset schizophrenia between chromosome 1q and 11q, t(1:11)(q43, were found to have 22q11 deletion in several sur- q21), which is associated with major mental ill- veys [26-31]. Our group also undertook screening ness in this family [40]. Subsequent molecular for 22q11 deletion in 177 schizophrenic patients genetic studies mapped the breakpoint sequence at from Taiwan [32]. We did not find any 22q11 de- chromosome 1 and identified two novel genes at letion in this sample; further study with larger 1q43 that were disrupted by this translocation, i.e. sample size is needed to clarify the prevalence rate Disrupted in Schizophrenia 1 (DISC1) and Dis- of 22q11 deletion in our schizophrenic population. rupted in Schizophrenia 2 (DISC2), respectively Taken together, these results indicate that the de- [41]. Subsequent association and linkage studies leted region of 22q11 in VCFS patients might har- showed that DISC1 gene is associated with bor important gene(s) for schizophrenia and other schizophrenia, schizoaffective, and bipolar dis- psychiatric disorders. The critical deleted region order in a North American white population [42], in some schizophrenic patients has been defined and linked to Finnish schizophrenia patients [43]. [26], which overlaps with the deleted region found However, DISC1 gene was not found to be associ- in VCFS patients with psychiatric disorders [33]. ated with schizophrenia in two studies in the Japa- Several genes in this region were considered can- nese population [44, 45]. In Taiwan, Liu and col- didate susceptible genes for schizophrenia and bi- leagues reported that DISC1 gene is associated polar disorders, such as catechol-O-methyltran- with schizophrenia with impaired sustained atten- sferase gene (COMT) [34], proline dehydro- tion as assessed by Continuous Performance Test genase gene (PRODH) [35], zinc finger- and [46]. There are three case-control studies examin- DHHC domain-containing 8 gene ing the association of DISC1 and schizophrenia in (ZDHHC8) [35], DGCR2 gene [36], TBX1 gene the Scottish population; one study did not find an [37], and PIK4CA gene [38]. Although the results association of DISC1 and DISC2 gene with of association studies of these genes with schizo- schizophrenia and bipolar affective disorder [47], phrenia are not unequivocal [39], at least, the one study found an association of DISC1 and fe- 22q11 deletion story tells us that chromosomal de- male bipolar disorder [48], and one study reported letion and duplication regions associated with an association of DISC1 and schizophrenia in schizophrenia are important sites to search for Scottish population, but with different pattern of schizophrenia genes. SNPs markers [49]. Although the association of Another consequence of chromosomal rear- DISC1 and schizophrenia is not conclusive yet, rangement is the translocation and inversion of the DISC1 story has prompted several research chromosome segments. Although the incidence of groups to undertake cytogenetic examination of chromosome segmental translocation and inver- patients with psychiatric disorders, which has led sion in schizophrenia is rare, the fine mapping and to the discovery of several genes associated with identification of breakpoint sequences can lead to psychiatric disorders. discovery of important genes for schizophrenia. At present time, there are more than ten Fang JS, Chen CH 247

genes identified through chromosome transloca- comparative genome hybridization (array CGH) tion in psychiatric disorders after DISC1 [50], was originally developed for detecting duplication several of them are associated with schizophrenia and deletion under fluorescent microscopy using or bipolar disorder. For example, phosphodiester- whole chromosomes as probes. Subsequently, ase 4B gene (PDE4B) at 1p31.2 was identified whole chromosomes were replaced with bacterial from a schizophrenic patient who has a balanced artificial chromosomes as probes, which provide translocation between chromosome 1 and 16, t (1; better resolution than whole chromosomes. Since 16)(p31.2;q21) [51]; kainite-type glutamate re- the accomplishment of the Human Genome Pro- ceptor gene (GRIK4) at chromosome 11q23.3, ject, synthetic oligonucleotide primers generated was discovered from a schizophrenic patient with from human genome sequences have been used mild learning disability, who has a complex chro- for probes, which can cover the whole human mosome rearrangement involving several chro- genome and allow comprehensive and unbiased mosomes [52]; NAPS3 gene at 14q13 that enco- detection of submicroscopic deletions and du- des a brain transcription factor, was identified plications of chromosomes. The resolution of from a family affected with schizophrenia and a oligonucleotide-based array CGH ranges from balanced translocation between chromosome 9 hundreds of bases to hundreds of thousands of and 14, t (9;14)(q34;q13) [53,54]. Two other ge- base pairs, depending on the inter-probe distance nes were found to be associated with bipolar dis- on the chip. Using this new technique, many pre- order through cytogenetic studies. One is manno- viously unidentified submicroscopic duplications syltransferase gene at 11q23 (DIBD1), which was and deletions were detected; some of them are found in a small family with bipolar affective dis- polymorphisms in human genome, while some are order and reciprocal chromosomal translocation t associated with diseases. Several groups have re- (9;11)(p24;q23) [55]; the other one is glutamate ported that they successfully detected many pre- receptor subunit 3 gene (GRIA3) at Xq24 from a viously undetected deletion and duplication in un- patient with bipolar affective disorder, mental re- explained mental retardation using array CGH tardation, who has a balanced translocation be- [57-59]. They suggest that array CGH is very tween chromosome X and 12, t (X;12)(q24;q15) useful for diagnosis of mental retardation. Jacque- [56]. Taken together, these results support the con- mont and colleagues (2006) studied 29 patients clusion that chromosomal translocations associ- with syndromic autism spectrum disorders, and ated with schizophrenia provide important clues identified 8 patients (27.5%) with deletions or du- to identify schizophrenia genes. plications in their chromosomes [60]. They pro- posed that array CGH is essential for the genetic Submicroscopic chromosome analysis of patients with syndromic autism spec- aberrations trum disorder. In a latest paper, Sebat and col- leagues (2007) reported an association of de novo Conventional karyotyping analysis has the copy number variations (CNVs) and autism spec- advantage of detecting chromosome aneuploidy, trum disorder using array CGH [61]. They identi- translocation, and inversion; however, it has fied CNVs in 12 out of 118 (10%) patients with limited resolution in detecting duplication and de- sporadic autism, and in 2 out of 77 (3%) patients letion sizes smaller than 3-5 million bases. Array with an affected first-degree relative, while only in 248 Cytogenetics and Schizophrenia

2 out 196 (1%) controls. Their findings support ray CGH seems to be a useful method to uncover that submicroscopic deletions and duplications of some previously undefined mutations in patients chromosomes are associated with autism, and ar- with schizophrenia, there should be an increasing ray CGH is an important tool to detect these appreciation of employing this new technique to CNVs. study the association of CNV and schizophrenia in To my knowledge, there are only two papers the future. published in the literature that report the associ- ation of DNA copy number variation (CNVs) in Implication and significance in patients with schizophrenia and bipolar disorders clinical and basic research using array CGH. Moon and colleagues analyzed DNA copy number changes in 30 patients with As elucidated in previous sections, although schizophrenia from Korea using bacterial artificial rare, chromosomal abnormalities such as translo- chromosome (BAC) array-based CGH, they iden- cation, deletion, duplication, and inversion do oc- tified several regions with DNA copy number cur in patients with schizophrenia, indicating that changes in their sample [62]. These regions with haplo-insufficiency (i.e. dysfunction of one of the DNA copy number changes were further confirm- two copies of gene) is an important genetic mechan- ed by real-time quantitative PCR. However, their ism of schizophrenia, which also fits the rare mu- association with schizophrenia is not clear, be- tation model of schizophrenia. Hence, it is likely cause they did not have control data in their study. that there are other types of mutations such as nu- Wilson and colleagues (2006) also employed cleotide substitutions or frame-shift mutations in BAC-based array CGH to assess the DNA copy single copies of genes that are severe enough to number changes in a sample consisting of patients cause schizophrenia. Mutation screening methods with schizophrenia and bipolar disorder and con- can be used for identification of these mutations. trol subjects [63]. They used genomic DNA iso- Genes identified from the region of chromo- lated from postmortem brains rather than that somal rearrangement can also be considered as from peripheral blood cells, because they claimed candidate susceptible genes for schizophrenia in that DNA from peripheral tissue can only reveal subsequent association and family linkage studies, constitutive changes, whereas brain DNA pro- which can complement genome-wide linkage and vides opportunity to detect somatic DNA copy association studies of schizophrenia. Genes do not number changes. They identified four loci with work alone in biological system; once a gene as- CNV in patients with schizophrenia and bipolar sociated with schizophrenia is identified, its re- disorder, but not in control subjects. Three out of lated genes such as genes in the same family, or these four loci were confirmed in a second cohort genes in the same functional pathway, or genes en- of psychiatric patients in their study. These CNV coding the interacting molecules, can also be con- loci contain genes GLUR7, CACNG2, and sidered as candidate genes for schizophrenia. For AKAP5, which are expressed in the brain and in- example, Hennah and colleagues reported that the volved in glutamate signaling. They suggested NDE1 gene that encodes an interacting protein that further scrutiny of these regions may reveal with DISC1, is also associated with Finnish insights into the etiology and genetic risk factors schizophrenia patients [64]. for complex psychiatric disorders. Thus, since ar- The identification of schizophrenia genes Fang JS, Chen CH 249

provides an important opportunity to interrogate these new techniques in clinical practice. the neurobiological basis of schizophrenia. Taking COMT as an example, COMT is located at the Summary critical region of interstitial deletion of 22q11, and is found to be associated with schizophrenia in The incidence of chromosomal abnormalities several studies. Based on its biochemical function may be rare in patients with schizophrenia using and its anatomic distribution in the brain, genetic conventional karyotype analysis. However, it may variants of COMT are proposed to be associated not be that rare when new techniques arrive with with impaired executive function in patients with better resolution. Furthermore, the mapping of the schizophrenia. Although recent meta-analysis breakpoint sequences and the identification of the does not support this association [65], at least re- susceptibility genes provide an opportunity to in- searchers are starting to have a target to explore terrogate the pathogenesis of schizophrenia at the the neurobiological basis of clinical dimensions of molecular and cellular levels. Hence, study of the schizophrenia. Similarly, after the finding that chromosomal aberrations in schizophrenic pati- DISC1 is associated with schizophrenia, research- ents is an important option or alternative to the ers are able to start to work on the molecular genome-wide association study and genetic link- mechanisms of schizophrenia with reference to age study of schizophrenia. DISC1 gene [66]. In the future, there will be more similar studies to decode the molecular mechan- References isms of schizophrenia in the literature. As more schizophrenia genes are identified, we will have a 1. Lichtermann D, Karbe E, Maier W: The genetic more comprehensive understanding of the whole epidemiology of schizophrenia and of schizo- picture of schizophrenia, which will ultimately phrenia spectrum disorders. Eur Arch Psychiatry lead to better treatment for schizophrenia. Clin Neurosci 2000;250:304-10. Conventional karyotype analysis is useful to 2. Sullivan PF: The genetics of schizophrenia. PLoS Med 2005;2:e212. detect aneupolidy and translocation, but it has 3. Faraone SV, Taylor L, Tsuang MT: The molecular some restrictions, such as limited resolution and genetics of schizophrenia: an emerging consensus. taking a long time to train experienced technici- Expert Rev Mol Med 2002;4:1-13. ans. However, when it is combined with new tech- 4. Fanous AH, Kendler KS: Genetic heterogeneity, nology such as fluorescent in situ hybridization modifier genes, and quantitative phenotypes in (FISH) and array comparative genome hybridiza- psychiatric illness: searching for a framework. tion (array CGH), the new molecular cytogenetics Mol Psychiatry 2005;10:6-13. becomes a powerful tool in detecting previously 5. WangWY,BarrattBJ,ClaytonDG,ToddJA: undetected chromosomal aberrations and identify- Genome-wide association studies: theoretical and ing schizophrenia genes [67]. These new tech- practical concerns. Nat Rev Genet 2005;6:109-18. niques are useful tools for research in the labora- 6. Reich DE, Lander ES: On the allelic spectrum of tory, and may have the potential to be used for cli- human disease. Trends Genet 2001;17:502-10. nical genetic testing of patients with schizo- 7. McClellan JM, Susser E, King MC: Schizo- phrenia in the future. More studies are needed to phrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 2007;190:194-9. investigate the diagnostic yield and feasibility of 250 Cytogenetics and Schizophrenia

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精神分裂症的細胞遺傳學研究

方菊雄 1 陳嘉祥 1,2,3,4

精神分裂症在臨床上是一種複雜的疾病， 精神分裂症病患做染色體檢查，但是隨著新技 在遺傳學上也屬複雜的疾病，因此精神分裂症 術的進步，新的分子細胞遺傳學變成一種很有 可說是複雜的遺傳性疾病。目前有幾種遺傳學 用的研究工具。文獻上有一些精神分裂症病患 上的方法來找精神分裂症的致病基因，像是聯 合併出現染色體異常，透過這些染色體異常的 鎖分析，全基因組相關分析，染色體檢查，與 研究找出精神分裂症的致病基因。此外最近有 基因體研究等。這些研究成果顯示精神分裂症 一種新的技術，Array comparative genome hy- 可能和很多基因都有相關，這些基因雖不會直 bridization (array CGH)，大大提升了偵測染色 接致病，但會增加或減少罹病的機會，精神分 體異常的解析度。透過這個方法，研究人員在 裂症可能是這些基因的交互作用所導致。另外 發展遲緩病患與精神病患身上發現一些過去未 精神分裂症也可能是單一基因突變所導致的， 被發現的染色體異常。因此結合傳統的細胞遺 這些突變比例可能不多，但嚴重到足以導致臨 傳學檢查與新的分子細胞遺傳學將使我們有機 床症狀的出現，而且不同病人的致病基因可能 會找到精神分裂症的致病基因，對精神分裂症 不同。精神分裂症合併出現染色體異常就是一 的致病機轉有新的了解，並且發展新的治療方 個例子，其發生率低，因此臨床醫師很少安排 法。

關鍵詞：精神分裂症，染色體異常，基因，病理 （台灣精神醫學 2007;21:242-53）

1 慈濟大學人類遺傳研究所 2 花蓮慈濟醫院精神醫學部 3 慈濟大學精神醫學科 4 國家衛生研究院精神醫學組 通信作者地址：陳嘉祥，970 花蓮市中央路 3 段 707 號 花蓮慈濟醫院精神醫學部