242 Taiwanese J Psychiatry Vol. 21 No. 4 2007 Chromosomal Abnormalities and Gene 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, chromosome analysis, and genomic study. Lilerature Reviews: The results from these studies show that schizophrenia can be associated with com- mon variants of many genes, 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 human genome, 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 chromosomes 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