0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Article   |    
Genome Scan of Han Chinese Schizophrenia Families From Taiwan: Confirmation of Linkage to 10q22.3
Stephen V. Faraone, Ph.D.; Hai-Gwo Hwu, M.D.; Chih-Min Liu, M.D.; Wei J. Chen, M.D., Sc.D.; Ming-Ming Tsuang, M.D.; Shih-Kai Liu, M.D.; Ming-Hsien Shieh, M.D.; Tzung-Jeng Hwang, M.D.; Wen-Chen Ou-Yang, Ph.D.; Chun-Ying Chen, M.D.; Chwen-Cheng Chen, M.D., Ph.D., M.R.C.Psych.; Jin-Jia Lin, M.D., M.P.H.; Frank Huang-Chih Chou, M.D., M.S., Ph.D.; Ching-Mo Chueh, M.D.; Wei-Ming Liu, M.D.; Mei-Hua Hall, M.S.; Jessica Su, Sc.D.; Paul Van Eerdewegh, Ph.D.; Ming T. Tsuang, D.Sc.
Am J Psychiatry 2006;163:1760-1766. doi:10.1176/appi.ajp.163.10.1760
Abstract

Objective: Genome-wide linkage analyses of schizophrenia have identified several regions that may harbor schizophrenia susceptibility genes, but given the complex etiology of the disorder, it is unlikely that all susceptibility regions have been detected. To address this issue, the authors ascertained 606 Han Chinese families comprising 1,234 affected members. Method: Probands with schizophrenia were recruited from six data collection field research centers in Taiwan. Each proband underwent a diagnostic screen with supplemental medical records and a semistructured interview. Following this screen, the authors administered the Mandarin Chinese version of the Diagnostic Interview for Genetic Studies. Best-estimate final diagnoses were made by two board-certified psychiatrists. The genotyping was conducted by the Center for Inherited Disease Research, with 386 markers spaced at an average of 9-centimorgan (cM) intervals. Empirical simulations were generated to determine genome-wide significance. Results: The authors found five regions with nonparametric linkage z scores 2.0 or greater. These were the following: 2.08 was reached for D1S551 (113.7) cM at 1p31.1 and 2.31 for D2S410 (125.2 cM) at 2q14.1; 2.00 was reached for D4S2361 (93.5 cM) at 4q21.23, and 2.07 for D15S1012 (36 cM) at 15q14, the largest nonparametric linkage z score was 2.88 for D10S2327 (100.92 cM) at 10q22.3. Conclusions: Our 10q22.3 finding at 100.9 cM is consistent with a previously reported nonparametric linkage score of 4.27 at 107.2 cM on chromosome 10, although it did not attain genome-wide significance in this study.

Abstract Teaser
Figures in this Article

Schizophrenia is a disabling mental disorder that affects 1% of the population worldwide (1). The symptoms of schizophrenia cause pervasive impairments in many domains of functioning and are costly in terms of the personal suffering of patients and families and the burden on the health care system. The symptoms and impairments of schizophrenia likely reflect neurodevelopmental deviations that lead to structural and functional anomalies in the frontal-subcortical circuits of the brain (2). Although the details of schizophrenia’s pathophysiology remain to be worked out, current evidence indicates that it is a complex disorder influenced by genes, environmental risk factors, and their interaction (3).

Over the past four decades, researchers have become increasingly certain that schizophrenia (Mendelian Inheritance in Man number 181500) has a complex multifactorial etiology (4–7). Among the relatives of patients, the risk for psychosis is about 50% of that of monozygotic twins—10% for first-degree relatives and 2% for second-degree relatives (3). A review of twin studies estimated the heritability of liability to schizophrenia to be 81% (8). And adoption studies show that schizophrenia is transmitted through biological rather than adoptive relationships (9–11). Despite this compelling evidence that genes influence susceptibility to schizophrenia, genome-wide linkage analyses of schizophrenia have produced conflicting results (12). Each of these linkage studies has identified regions showing some evidence for linkage to schizophrenia, but no finding has been consistently replicated.

One reason for conflicting results among prior studies is the use of relatively small samples. Risch and Merikangas (13) showed that linkage studies have low power for complex diseases where multiple genes of small effect lead to disease, and Suarez et al. (14) showed that, for genes of small effect, positive findings from small studies are unlikely to be replicated unless the replication sample is much larger. These considerations suggest that one approach to the difficulty of finding genes for schizophrenia is to collect a very large linkage sample of relatively homogeneous ethnicity using one set of methods. The present work took that approach and ascertained 557 Han Chinese families comprising 1,207 affected members. For comparison, the 20 schizophrenia linkage samples reviewed by Lewis et al. (12) had a mean of 60 families and 147 affected members.

Probands were recruited from six data collection field research centers throughout Taiwan. A detailed description of methods is given by Hwu et al. (15). To be included in the study, the family must have had two siblings with schizophrenia. We only included families of Han Chinese ancestry. Each proband underwent a diagnostic screen by a research psychiatrist using supplemental medical records and a semistructured interview that was based on DSM-IV (16).

Following this screen, the Mandarin Chinese version of the Diagnostic Interview for Genetic Studies (17–19) was administered. We used the Diagnostic Interview for Genetic Studies, which was created by two of the investigators (M.T.T. and S.V.F.) and colleagues from the NIMH Human Genetics Initiative because it had been recommended for use in the NIMH Request for Applications that funded the work. The Diagnostic Interview for Genetic Studies makes a detailed assessment of the course of illness and a careful assessment of substance abuse and mood symptoms. This allows for an easier differential diagnosis between schizophrenia and 1) substance-related psychoses, 2) schizoaffective disorders, and 3) psychotic mood disorders. This detailed assessment helps protect against false positive diagnoses. Nurnberger et al. (18) completed a reliability study of the Diagnostic Interview for Genetic Studies. Reliability for all individual diagnoses ranged from 0.73 to 0.95, except for schizoaffective disorder (0.29 and 0.49 for depressed and bipolar subtypes, respectively). Subsequent psychometric work by Faraone et al. (17) showed 1) that the low kappa was due to its low base rate, 2) that it was frequently confused with schizophrenia (but not with bipolar disorder), and 3) that it had low sensitivity but high specificity (which would not create false positive ascertainments).

The Diagnostic Interview for Genetic Studies interviewers were college graduates who had had a major in psychology or psychiatric nursing and, on average, clinical experience with psychiatric patients for 2 to 3 years. All of the Diagnostic Interview for Genetic Studies interviewers received a 4-week training course, including lectures on psychopathology, DSM-IV diagnostic criteria, practice interviews with psychiatric outpatients, and practice interviews with psychiatric inpatients. Six sessions of videotaped reliability testing were completed before participation in the data collection. We checked their ratings of selected Diagnostic Interview for Genetic Studies items from major sections (e.g., depression, mania, psychosis). We discussed any discrepancy with the trainees. If a trainee made any mistake in any axis I diagnosis or more than three errors in individual items, he or she was required to continue training.

We supplemented structured interview data with medical records and a semistructured itemized assessment of psychopathology in family members called the Family Instrument for Genetic Studies. Interviewers underwent rigorous training on the Diagnostic Interview for Genetic Studies and the Family Instrument for Genetic Studies to ensure an accurate diagnostic assessment. Best-estimate final diagnoses were made by two board-certified research psychiatrists independently based on all the clinical information that was collected. When these psychiatrists disagreed, a third diagnostician (H.-G.H.) resolved the disagreement by reviewing all data schedules and medical records, and if necessary, a discussion with the field psychiatrist who cared for the patient would be arranged for clarification of the clinical condition. For all subjects, the minimal set of information required to make a diagnosis comprised the Diagnostic Interview for Genetic Studies, the Family Instrument for Genetic Studies, and information from medical records. In addition, for each proband, we required data from the structured psychiatric screening interview. When diagnosing schizoaffective disorder, DSM-IV requires that “symptoms that meet criteria for a mood episode are present for a substantial portion of the total duration of active and residual periods.” We operationalized “substantial portion” as one-third or more, with the mood symptoms contributing to the functional impairments of the patient.

Genotyping was conducted by the Center for Inherited Disease Research, with 386 markers spaced at an average of 9-cM intervals, following the center’s standard genotyping procedures (http://www.cidr.jhmi.edu/protocol.html). The discordancy for duplicate genotypes assayed on the same plates as the study genotypes was 0.06%. Marker distances were generated by using the sex-averaged Marshfield genetic map (20). Mendelian inconsistencies were checked with the Genetic Analysis System, version 2.0 (21). RELCHECK was used to check for pedigree inconsistencies (22). The overall number of genotype and family errors was 0.39%.

Eleven discrepancies were found in six families. In two families, members thought to be full siblings were not and were excluded. In one family, a sibling was incorrectly coded as a parent, and the relationship was changed accordingly. Two individuals were found to be monozygotic twins, and therefore they were removed from the analysis. In one family, two parents were likely to be related by two or more degrees, so the family was excluded. The data reported here were collected through NIMH’s genetic initiative for schizophrenia. The genotypes and DNA samples are now publicly available and can be obtained through a formal request to NIMH. Clinical data are also available to the public. Details about how to access these data can be found at the following website: http://zork.wustl.edu/nimh.

Multipoint nonparametric genetic linkage analysis was performed on affected sibling pairs using the computer program MERLIN (23) (because of the study design, only sibling pairs were available). Siblings were analyzed simultaneously to assess allele sharing by descent. We report the nonparametric linkage z scores calculated from MERLIN described by Whittemore and Halpern (24). Nonparametric linkage z scores were calculated at all markers and at 1-cM increments throughout the genome. Allele frequencies were calculated in MERLIN by using all available individuals. In the analysis reported here, only individuals with schizophrenia were considered affected. When this analysis was performed with consideration of both individuals with schizophrenia and schizoaffective disorder as affected, the results were virtually identical to those presented here. Empirical simulation studies evaluated the genome-wide significance of our findings using MERLIN. MERLIN generates simulated chromosomes that have the original data structure with regard to marker informativeness, marker spacing, and missing data patterns. Data are generated under the null hypothesis of no linkage and no association to our phenotype—schizophrenia. One thousand simulations were generated to determine genome-wide significance.

We identified 883 potential families. Among these, 190 refused to participate, and 136 were excluded for various reasons, including too few family members, refusal to accept the data collection procedures, failure of one sibling to meet diagnostic criteria, death of the parent during the data collection period, and incomplete genotype information. Among the siblings in the sample, 1,234 had schizophrenia. Table 1 contains descriptive information for the 557 families used in the genetic linkage analysis.

We found five regions with nonparametric linkage z scores greater than or equal to 2.0 (Figure 1). These were 2.08 (p=0.02) for D1S551 (113.7 cM) at 1p31.1 and 2.31 (p=0.01) for D2S410 (125.2 cM) at 2q14.1; 2.00 (p=0.02) was reached for D4S2361 (93.5 cM) at 4q21.23 and 2.07 (p=0.02) for D15S1012 (36 cM) at 15q14. The largest nonparametric linkage z score was 2.88 (p=0.002) for D10S2327 (100.92 cM) at 10q22.3. Empirical simulations showed our largest finding did not reach genome-wide significance (p=0.14). Figure 2 shows the nonparametric linkage z scores for chromosome 10.

Figure 3 shows that many regions of the genome had relatively low information content. Less than 25% of the genome had information content greater than 0.75, and half of the genome had information content less than 0.67. Table 2 lists the peak nonparametric linkage z scores for each chromosome having uncorrected p values less than or equal to 0.05.

Our genome scan of Han Chinese families from Taiwan found evidence for a schizophrenia susceptibility gene at chromosome 10q22.3. Although our highest nonparametric linkage z score of 2.88 at 100.9 cM on chromosome 10 did not attain genome-wide significance, it provided statistically significant evidence for confirmed linkage, which was defined by Lander and Kruglyak (25) as achieving p<0.01 for a locus meeting criteria for genome-wide significant linkage in a prior study. For our chromosome 10 finding, it was the prior study of genome scanning of Ashkenazi Jewish families by Fallin et al. (26), which found a maximum nonparametric linkage score of 4.27 (p=0.00002) near marker D10S1744 at 107.2 cM on chromosome 10. The 95% CI for their region was 12.2 Mb, ranging from D10S1677 at 100.1 cM to D10S1753 at 112.6 cM. Considering that our finding was within this region, it seems reasonable to consider it as meeting the criteria of Lander and Kruglyak (25) for confirmed linkage. Although the convergence of linkage data on 10q is noteworthy because we did not attain genome-wide significance, firm conclusions regarding linkage of this region to schizophrenia must await fine-mapping efforts that may increase or decrease the evidence for genetic linkage.

In contrast to our apparent confirmation of the finding of Fallin et al. (26), two independent meta-analyses of schizophrenia linkage studies have not supported linkage to 10q22.3. Because the report by Fallin et al. (26) was completed subsequent to the meta-analyses, it did not contribute to the evidence for linkage. The multiple probability scan meta-analysis of 18 genome scans of Badner and Gershon (27) identified loci on chromosomes 8p, 13q, and 22q as showing strong evidence for linkage to schizophrenia. Other promising regions were 1q, 2q, 6q, and 15q, but evidence for linkage at these loci was weaker, indicating a need for further replication. Lewis et al. (12) applied genome scan meta-analysis to 20 schizophrenia genome scans. They found statistically genome-wide significant evidence for linkage to chromosome 2q. Their results also suggested the following regions to be strong candidates: 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p.

Our second largest finding was on chromosome 2q at 125.2 cM, which is located in the significant region reported by Lewis et al. (12). DeLisi et al. (28), Levinson et al. (29), and Moises et al. (30) all reported this region among their largest results, and positive findings were also reported by Coon et al. (31) and Straub et al. (32). Although these findings represent a broad region of chromosome 2, this area has consistently shown modest positive linkage findings. The linkage analysis in this article, which is one of the largest to date, also shows modest results in this region, suggesting that further, more detailed study is merited. Although our finding on chromosome 11 was modest, this region is ranked as the third strongest finding in the Lewis et al. meta-analysis. Also of note is our finding on chromosome 1, which is located in the region adjacent to the significant linkage reported by Brzustowicz et al. (33) and supported by Gurling et al. (34).

We considered the possibility that the differences between our study and the conclusions of the meta-analyses were due to our use of a Han Chinese sample. The possibility of disease gene heterogeneity across ethnic groups has not been systematically addressed in genetic linkage studies of schizophrenia. Because gene frequencies vary among racial groups, some functional polymorphisms may be more predominant in one group than another. And because of interactions with other genes or environmental risk factors, the same gene variant can have different functional consequences across racial groups.

Ethnic differences could also reflect systematic differences between the environments of racial groups in events such as obstetric complications, which are known to be risk factors for schizophrenia (35, 36). If a specific risk factor, such as anoxia, interacts with a specific susceptibility allele, then we would expect to find greater evidence of linkage for the race that has the greatest prevalence of anoxia. Such effects have been hypothesized to explain the increased prevalence and sibling concordance for schizophrenia among African Caribbeans in the United Kingdom (37).

Despite these considerations, there are several reasons why ethnicity is unlikely to account for our results. When examined separately, none of the prior studies showed evidence for linkage to 10q22.3, so it is not the case that the meta-analyses obscured a few significant findings at that locus. Fallin et al. (26) studied a sample of Ashkenazi Jewish families, and we studied Han Chinese families. Because we know of no clinical or epidemiological features of schizophrenia unique to these two ethnicities or any special population genetic relationship, it seems unlikely, a priori, that they would share a schizophrenia susceptibility gene not seen in other populations.

Other studies of Chinese samples argue against racial heterogeneity as an explanation for our results. None of these studies found evidence for linkage to 10q22.3 (38–42), but several found evidence of linkage to regions implicated by European-American samples. Examples include evidence by Hwu et al. (41) of linkage to 1q22-q31, the finding by Li et al. (40) at 22q11, the evidence of Hwu et al. (39) supporting linkage to 6p22-p24, the linkage evidence of Liu et al. (42) for 8p21, and the support of linkage for 15q13-14 by Liu et al. (38).

Our work should be viewed in the context of several limitations. The Diagnostic Interview for Genetic Studies interviewers had only 2 to 3 years of clinical experience. Although the Diagnostic Interview for Genetic Studies had been designed for use by interviewers with this level of training, the use of more experienced interviewers would have been better. This problem was also mitigated by the fact that all probands underwent a diagnostic screen by a research psychiatrist using supplemental medical records and a semistructured interview. Although our sample was very large, it may still not have sufficient power to detect susceptibility genes for schizophrenia in the presence of clinical and genetic heterogeneity, gene-environment interaction, and polygenic transmission.

The main strength of our study is its very large size. We collected 557 families comprising 1,207 affected members. In contrast, the 20 samples presented in the meta-analysis by Lewis et al. had a mean of 60 families and 147 affected members. Given this very large sample size, it is surprising that we did not find evidence for linkage to regions that have been implicated by prior studies. Although this may indicate that susceptibility regions implicated by prior studies are not relevant to the Han Chinese population, it is also possible that evidence for linkage was diminished by the main limitation of our study, i.e., the relatively low information content of the markers. Further work with a dense marker map is needed to evaluate this hypothesis.

Our results emphasize both the strengths and weaknesses of the linkage study method for schizophrenia. We have shown that a large sample can produce a result consistent with prior work but have also failed to replicate other findings. Thus, despite the progress achieved by our work and prior studies, all of this work was limited by the low power of linkage analysis for the finding of genes of small effect, a fact that has been previously noted (13).

+Received May 25, 2005; revision received Aug. 19, 2005; accepted Sept. 19, 2005. From the Genetics Research Program and the Department of Psychiatry and Behavioral Sciences, State University of New York Upstate Medical University; the Department of Psychiatry, National Taiwan University Hospital and Medical College, and the Department of Psychology, College of Science, National Taiwan University, Taipei; the Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei; the National Taoyuan Psychiatric Center and Ju-Shan Mental Hospital, Taoyuan, Taiwan; the National Chia-Nan Psychiatric Center, Tainan, Taipei; the Institute of Public Health, National Yang-Ming University, Taipei, Taiwan; the Department of Psychiatry, National Cheng-Kung University Hospital, Tainan, Taiwan; the Department of Psychiatry, Chimei Medical Center, Tainan, Taiwan; the Kai-Suan Psychiatric Hospital, Kaohsiung City, Taiwan; Yuli Veterans Hospital and National Yuli Hospital, Yuli, Taiwan; the Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, London; the Department of Epidemiology, Harvard School of Public Health, Boston; Genizon BioSciences, Montreal; the Department of Psychiatry and the Institute of Behavioral Genomics, University of California, San Diego; and Harvard Institute of Psychiatric Epidemiology and Genetics, Boston. Address correspondence and reprint requests to Dr. Faraone, Department of Psychiatry, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY 13210; faraones@upstate.edu (e-mail). Supported in part by NIMH grant 1R01-MH-59624-01 and by grants NHRI-90-8825PP and NHRI–EX91,92-9113PP from the National Health Research Institute, Taiwan, and the Genomic Medicine Research Program of Psychiatric Disorders, National Taiwan University Hospital.The authors thank the administrative authority of the Taiwan Schizophrenia Linkage Study group for their support, including the National Taoyuan, Chaotun, Yu-Li Psychiatric Center, National Cheng-Kung University Hospital, Kaohsiung Kai-Suan Psychiatric Hospital, Yu-Li Veteran Hospital, and Taipei City Psychiatric Center. The authors also thank the participating psychiatrists of the Taiwan Schizophrenia Linkage Study group for helping with the ascertainment of the study subjects; psychiatrists include Chiao-Chicy Chen, Jia-Jiu Lo, Jia-Fu Lee, Seng Shen, Yung Feng, Shin-Pin Lin, Shi-Chin Guo, Ming-Cheng Kuo, Liang-Jen Chuo, Chih-Pin Lu, Deng-Yi Chen, Huan-Kwang Ferng, Nan-Ying Chiu, Wen-Kun Chen, Tien-Cheng Lee, Hsin-Pei Tang, Yih-Dar Lee, Wu-Shih Wang, For-Wey Long, Tiao-Lai Huang, Jung-Kwang Wen, Cheng-Sheng Chen, Wen-Hsiang Huang, Shu-Yu Yang, Cheng-Hsing Chen. The authors also thank the hospitals that participated in this study: National Taiwan University Hospital and Medical College, National Taiwan University; National Taoyuan Psychiatric Center; National Tsaotun Psychiatric Center; National Cheng-Kung University; Kai-Suan Psychiatric Hospital, Kaohsiung City; and Yu-Li Veterans Hospital and National Yu-Li Hospital. Dr. Faraone has received grants from, acted as a consultant to, and been on the speaker’s bureau of Eli Lilly and Company and McNeil Consumer Pharmaceuticals. He has been a consultant to and been on the speaker’s bureau of Shire Pharmaceuticals and Cephalon, and he has been on the speaker’s bureau for Novartis Pharmaceutical. Dr. Hwu has received grants from Taiwan Otsuka Company, Eli Lilly and Company, and Taiwan Janssen Company for phase III clinical trials of antipsychotics. Dr. Hwang has received grants from Taiwan Otsuka Pharmaceutical Company, Taiwan Eli Lilly and Company, Taiwan Fujisawa Pharmaceutical Company, and Taiwan Janssen Pharmaceutical Company for phase III clinical trials of antipsychotics. Dr. Ou-Yang has received grants from Jassen-Cilag Taiwan and Johnson and Johnson for phase III clinical trials of antipsychotics. Dr. Chou has received grants from the National Science Council, ROC (Taiwan) for rescue workers" mental status, and mental health promotion. Drs. Liu, Wei J. Chen, Tsuang, Liu, Shieh, Chun-Ying Chen, Chwen-Cheng Chen, Lin, Chueh, Liu, Su, and Ms. Hall report no competing interests.

1.Tsuang MT, Faraone SV, Johnson P: Schizophrenia: The Facts. Oxford, UK, Oxford University Press, 1997
 
2.Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Toomey R, Tourville J, Kennedy D, Makris N, Caviness VS, Tsuang MT: Thalamic and amygdala-hippocampal volume reductions in first degree relatives of schizophrenic patients: an MRI-based morphometric analysis. Biol Psychiatry 1999; 46:941–954
 
3.Faraone SV, Glatt SJ, Taylor L: The genetic basis of schizophrenia, in Early Clinical Intervention and Prevention in Schizophrenia. Edited by Stone WS, Faraone SV, Tsuang MT. Totowa, NJ, Humana Press, 2004, pp 3–25
 
4.Gottesman I, Shields J: A polygenic theory of schizophrenia, in Proceedings of the National Academy of Sciences of the United States of America 1967; 58:199–205
 
5.Gottesman II: Twins: en route to QTLS for cognition. Science 1997; 276:1522–1523
 
6.Risch N: Linkage strategies for genetically complex traits, I: multilocus models. Am J Hum Genet 1990; 46:222–228
 
7.Faraone SV, Glatt SJ, Taylor L (eds): The Genetic Basis of Schizophrenia. Totowa, NJ, Humana Press, 2003
 
8.Sullivan PF, Kendler KS, Neale MC: Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60:1187–1192
 
9.Heston LL: Psychiatric disorders in foster home-reared children of schizophrenic mothers. Br J Psychiatry 1966; 112:819–825
 
10.Kety SS, Rosenthal D, Wender PH, Schulsinger F: The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. J Psychiatr Res 1968: 1(suppl):345–362
 
11.Kendler KS, Gruenberg AM, Kinney DK: Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish adoption study of schizophrenia. Arch Gen Psychiatry 1994; 51:456–468
 
12.Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T: Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 2003; 73:34–48
 
13.Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996; 273:1516–1517
 
14.Suarez BK, Hampe CL, Van Eerdewegh P: Problems of replicating linkage claims in psychiatry, in Genetic Approaches in Mental Disorders. Edited by Gershon ES, Cloninger CR, Barrett JE. Washington, DC, American Psychiatric Press, 1994, pp 23–46
 
15.Hwu HG, Faraone SV, Liu CM, Chen WJ, Liu SK, Shieh MH, Hwang TJ, Tsuang MM, Ou-Yang WC, Chen CY, Chen CC, Lin JJ, Chou FH, Chueh CM, Liu WM, Hall MH, Tsuang MT: Taiwan schizophrenia linkage study: the field study. Am J Med Genet B Neuropsychiatr Genet 2005; 134:30–36
 
16.American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Washington, DC, American Psychiatric Association, 1994
 
17.Faraone SV, Blehar M, Pepple J, Moldin S, Norton J, Tsuang MT, Nurnberger JI, Malaspina D, Kaufmann CA, Reich T, Cloninger CR, DePaulo JR, Berg K, Gershon ES, Kirch DG, Tsuang MT: Diagnostic accuracy and confusability analyses: an application to the diagnostic interview for genetic studies. Psychol Med 1996; 26:401–410
 
18.Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T, Miller M, Bowman ES, DePaulo JR, Cloninger CR, Robinson G, Moldin S, Gershon ES, Maxwell E, Guroff JJ, Kirch D, Wynne D, Berg K, Tsuang MT, Faraone SV, Pepple JR, Ritz AL: Diagnostic Interview for Genetic Studies: rationale, unique features, and training. Arch Gen Psychiatry 1994; 51:849–859
 
19.Chen WJ, Liu SK, Chang CJ, Lien YJ, Chang YH, Hwu HG: Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry 1998; 155:1214–1220
 
20.Broman KW, Murray JC, Sheffield VC, White RL, Weber JL: Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 1998; 63:861–869
 
21.Young A: Genetic Analysis System, 1995
 
22.Boehnke M, Cox NJ: Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 1997; 61:423–429
 
23.Abecasis GR, Cherny SS, Cookson WO, Cardon LR: MERLIN: rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30:97–101
 
24.Whittemore AS, Halpern J: A class of tests for linkage using affected pedigree members. Biometrics 1994; 50:118–127
 
25.Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11:241–247
 
26.Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE: Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 2003; 73:601–611
 
27.Badner J, Gershon E: Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7:405–411
 
28.DeLisi LE, Shaw SH, Crow TJ, Shields G, Smith AB, Larach VW, Wellman N, Loftus J, Nanthakumar B, Razi K, Stewart J, Comazzi M, Vita A, Heffner T, Sherrington R: A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159:803–812
 
29.Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A, Hayward NK, Crowe RR, Andreasen NC, Black DW, Silverman JM, Endicott J, Sharpe L, Mohs RC, Siever LJ, Walters MK, Lennon DP, Jones HL, Nertney DA, Daly MJ, Gladis M, Mowry BJ: Genome scan of schizophrenia. Am J Psychiatry 1998; 155:741–750
 
30.Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F, Arolt V, Blackwood D, Liu X, Sjogren B, et al: An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat Genet 1995; 11:321–324
 
31.Coon H, Worsley MM, Tiobech J, Hoff M, Rosenthal J, Bennett P, Reimherr F, Wender P, Dale P, Polloi A, Byerley W: Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol Psychiatry 1998; 3:521–527
 
32.Straub RE, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C, Wormley B, Sadek H, Kadambi B, O’Neill FA, Walsh D, Kendler KS: Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. Mol Psychiatry 2002; 7:542–559
 
33.Brzustowicz LM, Hodgkinson KA, Chow EWC, Honer WG, Basett AS: Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000; 288:678–682
 
34.Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS, Read T, Murphy P, Blaveri E, McQuillin A, Petursson H, Curtis D: Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68:661–673
 
35.Zornberg GL, Buka SL, Tsuang MT: The problem of obstetrical complications and schizophrenia. Schizophr Bull 2000; 26:249–256
 
36.Faraone SV, Brown CH, Glatt SJ, Tsuang MT: Preventing schizophrenia and psychotic behaviour: definitions and methodological issues. Can J Psychiatry 2002; 47:527–537
 
37.Hutchinson G, Takei N, Fahy TA, Bhugra D, Gilvarry C, Moran P, Mallett R, Sham P, Leff J, Murray RM: Morbid risk of schizophrenia in first-degree relatives of white and African-Caribbean patients with psychosis. Br J Psychiatry 1996; 169:776–780
 
38.Liu C, Hwu H, Lin M, Ou-Yang W, Lee S, Fann CSJ, Wong S, Hsieh S: Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13–14 in Taiwanese families. Am J Med Genetics (Neuropsychiatric Genetics) 2001; 105:658–661
 
39.Hwu HG, Lin MW, Lee PC, Lee SF, Ou-Yang WC, Liu CM: Evaluation of linkage of markers on chromosome 6p with schizophrenia in Taiwanese families. Am J Med Genetics (Neuropsychiatric Genetics) 2000; 96:74–78
 
40.Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, Collier DA: Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000; 5:77–84
 
41.Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF: Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 2003; 8:445–452
 
42.Liu CM, Hwu HG, Fann CS, Lin CY, Liu YL, Ou-Yang WC, Lee SF: Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. Am J Med Genet B Neuropsychiatr Genet 2005; 134:79–83
 
 
Figure 1. Genome-Wide Nonparametric Linkage z Scores for 557 Han Chinese Schizophrenia Families From Taiwana

aGenetic map distances from Marshfield (http://research.marshfieldclinic.org).

 
Figure 2. Nonparametric Linkage z Scores for Chromosome 10 for 557 Han Chinese Schizophrenia Families From Taiwana

aGenetic map distances from Marshfield (http://research.marshfieldclinic.org).

 
Figure 3. Genome-Wide Information Content for 557 Han Chinese Schizophrenia Families From Taiwana

aGenetic map distances from Marshfield (http://research.marshfieldclinic.org).

bMeasure of how informative a marker or a map of markers is in a collection of pedigrees in order to extract the maximum amount of inheritance information for a linkage analysis (http://www.illumina.com/products/snp/snp_linkage_content.ilmn).

Figure 1. Genome-Wide Nonparametric Linkage z Scores for 557 Han Chinese Schizophrenia Families From Taiwana

aGenetic map distances from Marshfield (http://research.marshfieldclinic.org).

Figure 2. Nonparametric Linkage z Scores for Chromosome 10 for 557 Han Chinese Schizophrenia Families From Taiwana

aGenetic map distances from Marshfield (http://research.marshfieldclinic.org).

Figure 3. Genome-Wide Information Content for 557 Han Chinese Schizophrenia Families From Taiwana

aGenetic map distances from Marshfield (http://research.marshfieldclinic.org).

bMeasure of how informative a marker or a map of markers is in a collection of pedigrees in order to extract the maximum amount of inheritance information for a linkage analysis (http://www.illumina.com/products/snp/snp_linkage_content.ilmn).

+

References

1.Tsuang MT, Faraone SV, Johnson P: Schizophrenia: The Facts. Oxford, UK, Oxford University Press, 1997
 
2.Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Toomey R, Tourville J, Kennedy D, Makris N, Caviness VS, Tsuang MT: Thalamic and amygdala-hippocampal volume reductions in first degree relatives of schizophrenic patients: an MRI-based morphometric analysis. Biol Psychiatry 1999; 46:941–954
 
3.Faraone SV, Glatt SJ, Taylor L: The genetic basis of schizophrenia, in Early Clinical Intervention and Prevention in Schizophrenia. Edited by Stone WS, Faraone SV, Tsuang MT. Totowa, NJ, Humana Press, 2004, pp 3–25
 
4.Gottesman I, Shields J: A polygenic theory of schizophrenia, in Proceedings of the National Academy of Sciences of the United States of America 1967; 58:199–205
 
5.Gottesman II: Twins: en route to QTLS for cognition. Science 1997; 276:1522–1523
 
6.Risch N: Linkage strategies for genetically complex traits, I: multilocus models. Am J Hum Genet 1990; 46:222–228
 
7.Faraone SV, Glatt SJ, Taylor L (eds): The Genetic Basis of Schizophrenia. Totowa, NJ, Humana Press, 2003
 
8.Sullivan PF, Kendler KS, Neale MC: Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60:1187–1192
 
9.Heston LL: Psychiatric disorders in foster home-reared children of schizophrenic mothers. Br J Psychiatry 1966; 112:819–825
 
10.Kety SS, Rosenthal D, Wender PH, Schulsinger F: The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. J Psychiatr Res 1968: 1(suppl):345–362
 
11.Kendler KS, Gruenberg AM, Kinney DK: Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish adoption study of schizophrenia. Arch Gen Psychiatry 1994; 51:456–468
 
12.Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T: Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 2003; 73:34–48
 
13.Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996; 273:1516–1517
 
14.Suarez BK, Hampe CL, Van Eerdewegh P: Problems of replicating linkage claims in psychiatry, in Genetic Approaches in Mental Disorders. Edited by Gershon ES, Cloninger CR, Barrett JE. Washington, DC, American Psychiatric Press, 1994, pp 23–46
 
15.Hwu HG, Faraone SV, Liu CM, Chen WJ, Liu SK, Shieh MH, Hwang TJ, Tsuang MM, Ou-Yang WC, Chen CY, Chen CC, Lin JJ, Chou FH, Chueh CM, Liu WM, Hall MH, Tsuang MT: Taiwan schizophrenia linkage study: the field study. Am J Med Genet B Neuropsychiatr Genet 2005; 134:30–36
 
16.American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Washington, DC, American Psychiatric Association, 1994
 
17.Faraone SV, Blehar M, Pepple J, Moldin S, Norton J, Tsuang MT, Nurnberger JI, Malaspina D, Kaufmann CA, Reich T, Cloninger CR, DePaulo JR, Berg K, Gershon ES, Kirch DG, Tsuang MT: Diagnostic accuracy and confusability analyses: an application to the diagnostic interview for genetic studies. Psychol Med 1996; 26:401–410
 
18.Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T, Miller M, Bowman ES, DePaulo JR, Cloninger CR, Robinson G, Moldin S, Gershon ES, Maxwell E, Guroff JJ, Kirch D, Wynne D, Berg K, Tsuang MT, Faraone SV, Pepple JR, Ritz AL: Diagnostic Interview for Genetic Studies: rationale, unique features, and training. Arch Gen Psychiatry 1994; 51:849–859
 
19.Chen WJ, Liu SK, Chang CJ, Lien YJ, Chang YH, Hwu HG: Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry 1998; 155:1214–1220
 
20.Broman KW, Murray JC, Sheffield VC, White RL, Weber JL: Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 1998; 63:861–869
 
21.Young A: Genetic Analysis System, 1995
 
22.Boehnke M, Cox NJ: Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 1997; 61:423–429
 
23.Abecasis GR, Cherny SS, Cookson WO, Cardon LR: MERLIN: rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30:97–101
 
24.Whittemore AS, Halpern J: A class of tests for linkage using affected pedigree members. Biometrics 1994; 50:118–127
 
25.Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11:241–247
 
26.Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE: Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 2003; 73:601–611
 
27.Badner J, Gershon E: Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7:405–411
 
28.DeLisi LE, Shaw SH, Crow TJ, Shields G, Smith AB, Larach VW, Wellman N, Loftus J, Nanthakumar B, Razi K, Stewart J, Comazzi M, Vita A, Heffner T, Sherrington R: A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159:803–812
 
29.Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A, Hayward NK, Crowe RR, Andreasen NC, Black DW, Silverman JM, Endicott J, Sharpe L, Mohs RC, Siever LJ, Walters MK, Lennon DP, Jones HL, Nertney DA, Daly MJ, Gladis M, Mowry BJ: Genome scan of schizophrenia. Am J Psychiatry 1998; 155:741–750
 
30.Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F, Arolt V, Blackwood D, Liu X, Sjogren B, et al: An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat Genet 1995; 11:321–324
 
31.Coon H, Worsley MM, Tiobech J, Hoff M, Rosenthal J, Bennett P, Reimherr F, Wender P, Dale P, Polloi A, Byerley W: Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol Psychiatry 1998; 3:521–527
 
32.Straub RE, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C, Wormley B, Sadek H, Kadambi B, O’Neill FA, Walsh D, Kendler KS: Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. Mol Psychiatry 2002; 7:542–559
 
33.Brzustowicz LM, Hodgkinson KA, Chow EWC, Honer WG, Basett AS: Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000; 288:678–682
 
34.Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS, Read T, Murphy P, Blaveri E, McQuillin A, Petursson H, Curtis D: Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68:661–673
 
35.Zornberg GL, Buka SL, Tsuang MT: The problem of obstetrical complications and schizophrenia. Schizophr Bull 2000; 26:249–256
 
36.Faraone SV, Brown CH, Glatt SJ, Tsuang MT: Preventing schizophrenia and psychotic behaviour: definitions and methodological issues. Can J Psychiatry 2002; 47:527–537
 
37.Hutchinson G, Takei N, Fahy TA, Bhugra D, Gilvarry C, Moran P, Mallett R, Sham P, Leff J, Murray RM: Morbid risk of schizophrenia in first-degree relatives of white and African-Caribbean patients with psychosis. Br J Psychiatry 1996; 169:776–780
 
38.Liu C, Hwu H, Lin M, Ou-Yang W, Lee S, Fann CSJ, Wong S, Hsieh S: Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13–14 in Taiwanese families. Am J Med Genetics (Neuropsychiatric Genetics) 2001; 105:658–661
 
39.Hwu HG, Lin MW, Lee PC, Lee SF, Ou-Yang WC, Liu CM: Evaluation of linkage of markers on chromosome 6p with schizophrenia in Taiwanese families. Am J Med Genetics (Neuropsychiatric Genetics) 2000; 96:74–78
 
40.Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, Collier DA: Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000; 5:77–84
 
41.Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF: Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 2003; 8:445–452
 
42.Liu CM, Hwu HG, Fann CS, Lin CY, Liu YL, Ou-Yang WC, Lee SF: Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. Am J Med Genet B Neuropsychiatr Genet 2005; 134:79–83
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 46

Related Content
Articles
Books
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 4th Edition > Chapter 6.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles