- Open Access
Susceptibility of schizophrenia and affective disorder not associated with loci on chromosome 6q in Han Chinese population
Behavioral and Brain Functions volume 3, Article number: 46 (2007)
Several linkage studies across multiple population groups provide convergent support for susceptibility loci for schizophrenia – and, more recently, for affective disorder – on chromosome 6q. We explore whether schizophrenia and affective disorder have common susceptibility gene on 6q in Han Chinese population.
In the present study, we genotyped 45 family trios from Han Chinese population with mixed family history of schizophrenia and affective disorder. Twelve short tandem repeat (STRs) markers were selected, which covered 102.19 cM on chromosome 6q with average spacing 9.29 cM and heterozygosity 0.78. The transmission disequilibrium test (TDT) was performed to search for susceptibility loci to schizophrenia and affective disorder.
The results showed STRs D6S257, D6S460, D6S1021, D6S292 and D6S1581 were associated with susceptibility to psychotic disorders. When families were grouped into schizophrenia and affective disorder group, D6S257, D6S460 and D6S1021, which map closely to the centromere of chromosome 6q, were associated with susceptibility to schizophrenia. Meanwhile, D6S1581, which maps closely to the telomere, was associated with susceptibility to affective disorder. But after correction of multiple test, all above association were changed into no significance (P > 0.05).
These results suggest that susceptibility of schizophrenia and affective disorder not associated with loci on chromosome 6q in Han Chinese population.
The distinction between schizophrenia and affective disorder was historically based on distinct phenomenologies and long-term courses. A differential nosology and etiology was postulated, however never convincingly proven . Opinions vary as to whether these disorders are etiologically distinct or represent points on a continuum of liability. Speculating from Kraepelin's view, schizophrenia does not aggregate in families of affective illness patients nor is there increased incidence of mood disorder in relatives of chronic schizophrenics. However, Rudin found risks of suffering from schizophrenia and mood disorder did not differ significantly among schizophrenic sibs . Subsequently investigators found an increased risk of schizophrenic spectrum disorders among the first-degree relatives of probands with a family history of major mood disorders . Conversely, relatives of probands with a family history of schizophrenic spectrum disorders were at a greater risk of affective illness than relatives of probands with no family history. Increasing evidence from molecular genetics also suggests an overlap in genetic susceptibility across the traditional classification systems. This has been suggested for linkage regions: 6q12-25, 13q32-q34 and 22q11-q22, and specific genes: DAOA(G72), DISC1, and NRG1 .
Several linkage studies across multiple population groups provide convergent support for susceptibility loci for schizophrenia – and, more recently, for affective disorder – on chromosome 6q. The first report of linkage findings on 6q13-26 in schizophrenia came from  which has accumulated support from a number of studies [6–17]. Recently, susceptibility loci to affective disorder were also reported to map to 6q [12, 18–29], reviewed these results of positive linkage and association, and concluded that five regions (~91 Mb, ~113 Mb, ~126 Mb, ~133 Mb and ~162 Mb) could harbor susceptibility gene(s) to both schizophrenia and affective disorder. These phenomena lend support to the notion that affective disorder or a subset is associated with the liability to schizophrenia on chromosome 6q. In order to investigate whether schizophrenia and affective disorder have some genetic relationship on chromosome 6q, we recruited family trios with mixed family history of schizophrenia and affective disorder from the Han Chinese population for study using the transmission disequilibrium test (TDT).
A mixed family was defined as one in which members suffer from both schizophrenia and affective disorder separately, namely at least one patient with schizophrenia and another patient with affective disorder among three-generation relatives. We recruited 45 family trios, composed of the probands and their biological parents, with mixed family history of schizophrenia and affective disorder. Here the probands were outpatients or inpatients from Shanghai Mental Health Center. Clinical diagnosis was made according to ICD-10; an independent clinician using the same criteria reviewed all diagnoses. Blood samples were obtained from the family trios. The investigation was carried out in accordance with the latest version of the Declaration of Helsinki, that the study design was reviewed by an appropriate ethical committee and that informed consent of the participants was obtained after the nature of the procedures had been fully explained. The probands included 21 male patients and 24 female ones, 26 diagnosed with schizophrenia and 19 with affective disorder (including 6 diagnosed with depressive disorder and 13 with single manic episode, respectively), mean age of patients were 28.7 ± 8.9 years, mean age of onset were 22.7 ± 8.0 years, mean duration were 5.9 ± 6.4 years; and the mean age of their parents were 58.5 ± 10.4 years.
Genomic DNA was extracted from peripheral blood leukocytes of each subject. The short tandem repeat (STR) markers used in this study were modified from the ABI PRISM Linkage Mapping Set Version 2.5. These included 12 STRs (D6S257, D6S460, D6S462, D6S1021, D6S1698, D6S1639, D6S262, D6S292, D6S308, D6S441, D6S1581, D6S1697) on chromosome 6q, which spanned 102.19 cM with a mean interval of 9.29 cM, heterozygosity of each STR above 0.50 and average heterozygosity 0.78 (see Table 1). Markers were amplified by polymerase chain reaction (PCR) with a Gene Amp PCR System 9700 (Perkin-Elmer, Foster City, CA). Electrophoresis was performed with an ABI PRISM 3730 sequencer (Perkin-Elmer). The PCR products were genotyped with ABI GeneMapper software (Perkin-Elmer).
Hardy-Weinberg equilibrium and statistical differences in genotype and allele frequencies between probands and parents were evaluated using the χ2 test at a significance level of 0.05. Family-based association analyses was performed with applying the transmission disequilibrium test (TDT), where preferential allelic transmission from heterozygous parents to affected offspring is tested by applying (b-c)2/(b+c) statistics (Mc Nemar's equation) and χ2 test.
The genotype distributions of total markers in the patient group and parent group did not deviate significantly from Hardy-Weinberg equilibrium in the patient or parent group (P > 0.05). Taking all family trios as study subjects, we found five STRs D6S257 at 79.92 cM, D6S460 at 89.83 cM, D6S1021 at 112.20 cM, D6S292 at 136.97 cM and D6S1581 at 164.78 cM were associated with susceptibility to psychotic disorders (see table 2). Then the family trios were grouped into schizophrenia group and affective disorder group according to diagnoses of probands and analyzed separately by TDT. We found that D6S257, D6S460 and D6S1021, which map closely to the centromere of chromosome 6q, were associated with susceptibility to schizophrenia. Meanwhile, D6S1581, which maps closely to the telomere, was associated with susceptibility to affective disorder. But after correction of multiple test, all above association were changed into no significance (P > 0.05).
Heretofore the pathogenesis of schizophrenia and affective disorder have been unclear. Evidence from family, twin and adoption studies indicate that both genetic and environmental factors are involved in the etiology of these diseases. Molecular genetics studies suggest that they may be heterogenous and polygenic diseases. Despite the widely accepted view that schizophrenia and affective disorder represent independent illnesses and have different modes of inheritance, some data in the literature suggest that these diseases may share some genetic susceptibility. Many linkage analyses have suggested that the chromosome 6q region could harbor susceptibility loci to schizophrenia. Recently loci for affective disorder were reported to map in the 6q region. These results suggest that the relationship between chromosome 6q and susceptibility to schizophrenia or affective disorder deserves further study. Craddock et al  by meta-analysis and Kohn et al  by a topographic approach reviewed all reported results, and both concluded similarly that susceptibility genes to schizophrenia and affective disorder may both be located on chromosome 6q. Ewald et al  and Dick et al  reported positive linkage between D6S1021 and susceptibility to affective disorder.
The present study was performed in mixed pedigrees for schizophrenia and affective disorder to investigate whether two diseases share common genetic loci on 6q. Though primary results showed STRs D6S257, D6S460, D6S1021, D6S292 and D6S1581 were associated with susceptibility to psychotic disorders. Further grouped analysis showed that D6S257, D6S460 and D6S1021 were associated with susceptibility to schizophrenia, D6S1581 associated with susceptibility to affective disorder. But after correction of multiple tests, there is no significance association between loci on 6q and susceptibility of psychiatric disorders, including schizophrenia or affective disorder. These results suggest that susceptibility of schizophrenia and affective disorder not associated with loci on chromosome 6q in Han Chinese population. One of most limitations for the study is small sample size because of the mixed family trios with schizophrenia and affective disorders correspondingly too mall. For the reason, we did not differentiate the mean age of patients, mean age at onset, mean duration, etc. for both disorders to analyze. This and differences in population, allelic and locus heterogeneity may explain our inability to replicate some previous results. Future study is needed to collect a larger number of better-characterized trios in different population and avoid false negative association.
These results suggest that susceptibility of schizophrenia and affective disorder not associated with loci on chromosome 6q in our family trios of Han Chinese population.
Maier W, Hofgen B, Zobel A, Rietschel M: Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes?. Eur Arch Psychiatry Clin Neurosci. 2005, 255: 159-166. 10.1007/s00406-005-0583-9.
Tsuang MT, Winokur G, Crowe RR: Morbidity risks of schizophrenia and affective disorders among first-degree relatives of patients with schizophrenia, mania, depression and surgical conditions. Br J Psychiatry. 1980, 137: 497-504.
Baron M, Gruen RS: Schizophrenia and affective disorder: are they genetically linked ?. Br J Psychiatry. 1991, 159: 267-270.
Craddock N, O'Donovan MC, Owen MJ: The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet. 2005, 42: 193-204. 10.1136/jmg.2005.030718.
Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A, Markey CJ, Beshah E, Guroff JJ, Maxwell ME, Kazuba DM, Whiten R, Goldin LR, Gershon ES, Gejman PV: Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics. 1997, 43: 1-8. 10.1006/geno.1997.4815.
Martinez M, Goldin LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ, Taylor JM, Levinson DF, Kirby A, Crowe RR, Andreasen NC, Black DW, Silverman JM, Lennon DP, Nertney DA, Brown DM, Mowry BJ, Gershon ES, Gejman PV: Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q. Am J Med Genet. 1999, 88: 337-343. 10.1002/(SICI)1096-8628(19990820)88:4<337::AID-AJMG9>3.0.CO;2-A.
Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD, Meyer J, Zambuto CT, Schmitt K, Matise TC, Harkavy Friedman JM, Hampe C, Lee H, Shore D, Wynne D, Faraone SV, Tsuang MT, Cloninger CR: NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet. 1998, 81: 282-289. 10.1002/(SICI)1096-8628(19980710)81:4<282::AID-AJMG2>3.0.CO;2-W.
Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV, Pulver AE, Laurent C, Kendler KS, Walsh D, Norton N, Williams NM, Schwab SG, Lerer B, Mowry BJ, Sanders AR, Antonarakis SE, Blouin JL, DeLeuze JF, Mallet J: Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. Am J Hum Genet. 2000, 67: 652-663. 10.1086/303041.
Bailer U, Leisch F, Meszaros K, Lenzinger E, Willinger U, Strobl R, Gebhardt C, Gerhard E, Fuchs K, Sieghart W, Kasper S, Hornik K, Aschauer HN: Genome scan for susceptibility loci for schizophrenia. Neuropsychobiology. 2000, 42: 175-182. 10.1159/000026690.
Edgar PF, Douglas JE, Cooper GJ, Dean B, Kydd R, Faull RLl: Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia. Mol Psychiatry. 2000, 5: 85-90. 10.1038/sj.mp.4000580.
Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, Pettersson U, Sherrington R, Adolfsson R, Jazin E: A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees. Am J Hum Genet. 2001, 69: 96-105. 10.1086/321288.
Bailer U, Leisch F, Meszaros K, Lenzinger E, Willinger U, Strobl R, Heiden A, Gebhardt C, Doge E, Fuchs K, Sieghart W, Kasper S, Hornik K, Aschauer HN: Genome scan for susceptibility loci for schizophrenia and bipolar disorder. Biol Psychiatry. 2002, 52: 40-52. 10.1016/S0006-3223(02)01320-3.
Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y, Chowdari KV, Cardno AG, Zammit S, Jones LA, Murphy KC, Sanders RD, McCarthy G, Gray MY, Jones G, Holmans P, Nimgaonkar V, Adolfson R, Osby U, Terenius L, Sedvall G, O'Donovan MC, Owen MJ: A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet. 2003, 73: 1355-1367. 10.1086/380206.
Lerer B, Segman RH, Hamdan A, Kanyas K, Karni O, Kohn Y, Korner M, Lanktree M, Kaadan M, Turetsky N, Yakir A, Kerem B, Macciardi F: Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry. 2003, 8: 488-498. 10.1038/sj.mp.4001322.
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: Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet. 2003, 73: 34-48. 10.1086/376549.
Duan J, Martinez M, Sanders AR, Hou C, Saitou N, Kitano T, Mowry BJ, Crowe RR, Silverman JM, Levinson DF, Gejman PV: Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am J Hum Genet. 2004, 75: 624-638. 10.1086/424887.
Levi A, Kohn Y, Kanyas K, Amann D, Pae CU, Hamdan A, Segman RH, Avidan N, Karni O, Korner M, Jun TY, Beckmann JS, Macciardi F, Lerer B: Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval. Eur J Hum Genet. 2005, 13: 763-771. 10.1038/sj.ejhg.5201406.
Bennett P, Segurado R, Jones I, Bort S, McCandless F, Lambert D, Heron J, Comerford C, Middle F, Corvin A, Pelios G, Kirov G, Larsen B, Mulcahy T, Williams N, O'Connell R, O'Mahony E, Payne A, Owen M, Holmans P, Craddock N, Gill M: The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report. Mol Psychiatry. 2002, 7: 189-200. 10.1038/sj.mp.4000957.
Ewald H, Flint T, Kruse TA, Mors O: A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3. Mol Psychiatry. 2002, 7: 734-744. 10.1038/sj.mp.4001074.
Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL, Moe PR, Samavedy N, El-Mallakh R, Manji H, Glitz DA, Meyer ET, Smiley C, Hahn R, Widmark C, McKinney R, Sutton L, Ballas C, Grice D, Berrettini W, Byerley W, Coryell W, DePaulo R, MacKinnon DF, Gershon ES, Kelsoe JR, McMahon FJ, McInnis M, Murphy DL, Reich T: Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet. 2003, 73: 107-114. 10.1086/376562.
McInnis MG, Dick DM, Willour VL, Avramopoulos D, MacKinnon DF, Simpson SG, Potash JB, Edenberg HJ, Bowman ES, McMahon FJ, Smiley C, Chellis JL, Huo Y, Diggs T, Meyer ET, Miller M, Matteini AT, Rau NL, DePaulo JR, Gershon ES, Badner JA, Rice JP, Goate AM, Detera-Wadleigh SD, Nurnberger JI, Reich T, Zandi PP, Foroud TM: Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees. Biol Psychiatry. 2003, 54: 1265-1273. 10.1016/j.biopsych.2003.08.001.
Schulze TG, Buervenich S, Badner JA, Steele CJ, Detera-Wadleigh SD, Dick D, Foroud T, Cox NJ, MacKinnon DF, Potash JB, Berrettini WH, Byerley W, Coryell W, DePaulo JR, Gershon ES, Kelsoe JR, McInnis MG, Murphy DL, Reich T, Scheftner W, Nurnberger JI, McMahon FJ: Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees. Biol Psychiatry. 2004, 56: 18-23. 10.1016/j.biopsych.2004.04.004.
Pato CN, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Verner A, Hudson TJ, Morley CP, Kennedy JL, Azevedo MH, Daly MJ, Sklar P: Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11. Am J Med Genet B Neuropsychiatr Genet. 2004, 127: 30-34. 10.1002/ajmg.b.30001.
Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF, Brown A, Petryshen TL, Kirby AN, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Azevedo MH, Kennedy JL, Daly MJ, Sklar P, Pato CN: Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet. 2004, 74: 886-897. 10.1086/420775.
Park N, Juo SH, Cheng R, Liu J, Loth JE, Lilliston B, Nee J, Grunn A, Kanyas K, Lerer B, Endicott J, Gilliam TC, Baron M: Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia. Mol Psychiatry. 2004, 9: 1091-1099. 10.1038/sj.mp.4001541.
Park N, Cheng R, Juo SH, Liu J, Loth JE, Endicott J, Gilliam TC, Baron M: Absence of psychosis may influence linkage results for bipolar disorder. Mol Psychiatry. 2005, 10: 235-237. 10.1038/sj.mp.4001623.
Venken T, Claes S, Sluijs S, Paterson AD, van Duijn C, Adolfsson R, Del-Favero J, Van Broeckhoven C: Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population. Am J Hum Genet. 2005, 76: 237-248. 10.1086/427836.
Abou Jamra R, Sircar I, Becker T, Freudenberg-Hua Y, Ohlraun S, Freudenberg J, Brockschmidt F, Schulze TG, Gross M, Spira F, Deschner M, Schmäl C, Maier W, Propping P, Rietschel M, Cichon S, Nöthen MM, Schumacher J: A family-based and case-control association study of trace amine receptor genes on chromosome 6q23 in bipolar affective disorder. Mol Psychiatry. 2005, 10: 618-620. 10.1038/sj.mp.4001665.
Kohn Y, Lerer B: Excitement and confusion on chromosome 6q: the challenges of neuropsychiatriatric genetics in microcosm. Mol Psychiatry. 2005, 10: 1062-1073. 10.1038/sj.mp.4001738.
The National Natural Science Foundation (China, No 30270494), The Funds for Key Program in the National "10th 5-year Plan" of China (No 2004BA720A21-02), and the "863" Program of China (No 2006AA02Z430) supported this work for scientific research. We acknowledge Prof. Stephen V. Faraone (a BBF Editorial Board member) who gives some important suggestions in reviewing manuscript.
The author(s) declare that they have no competing interests.
Dr. Zuowei Wang and Prof. Yiru Fang participated in the design of the study and drafting the manuscript. Dr. Zuowei and Dr. Shunying Yu carried out the molecular genetic studies, participated in the sequence alignment and performed the statistical analysis. Dr. ChengMei Yuan Dr. Wu Hong, Dr. Zhenghui Yi, Prof. Sanduo Jiang and Prof. Zucheng Wang participated in sample collection. Prof. John R. Kelsoe helped to review the manuscript. All authors read and approved the final manuscript.
About this article
Cite this article
Wang, Z., Fang, Y., Yu, S. et al. Susceptibility of schizophrenia and affective disorder not associated with loci on chromosome 6q in Han Chinese population. Behav Brain Funct 3, 46 (2007) doi:10.1186/1744-9081-3-46
- Affective Disorder
- Short Tandem Repeat
- Susceptibility Locus
- Psychotic Disorder