Abstract
Chromosome 22 has been implicated in schizophrenia and bipolar disorder in a number of linkage, association and cytogenetic studies. Recent evidence has also implicated CAG repeat tract expansion in these diseases. In order to explore the involvement of CAG repeats on chromosome 22 in these diseases, we have created an integrated map of all CAG repeats ≥5 on this chromosome together with microsatellite markers associated with these diseases using the recently completed nucleotide sequence of chromosome 22. Of the 52 CAG repeat loci identified in this manner, four of the longest repeat stretches in regions previously implicated by linkage analyses were chosen for further study. Three of the four repeat containing loci, were found in the coding region with the CAG repeats coding for glutamine and were expressed in the brain. All the loci studied showed varying degrees of polymorphism with one of the loci exhibiting two alleles of 7 and 8 CAG repeats. The 8-repeat allele at this locus was significantly overrepresented in both schizophrenia and bipolar patient groups when compared to ethnically matched controls, while alleles at the other three loci did not show any such difference. The repeat lies within a gene which shows homology to an androgen receptor related apoptosis protein in rat. We have also identified other candidate genes in the vicinity of this locus. Our results suggest that the repeats within this gene or other genes in the vicinity of this locus are likely to be implicated in bipolar disorder and schizophrenia.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gottesman I . Schizophrenia Genesis: The Origins of Madness WH Freeman and Company: New York 1991
Karayiorgou M, Gogos JA . A turning point in schizophrenia genetics Neuron 1997 19: 967–979
Riley BP, McGuffin P . Linkage and associated studies of schizophrenia Am J Med Genet 2000 97: 23–44
Schwab SG, Wildenauer DB . Chromosome 22 workshop report Am J Med Genet 1999 88: 276–278
Coon H, Jensen S, Holik J, Hoff M, Myles-Worsley M, Reimherr F et al. Genomic scan for genes predisposing to schizophrenia Am J Med Genet 1994 54: 59–71
Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter VK, Kasch L, Nestadt G et al. Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1 Am J Med Genet 1994 54: 36–43
Schizophrenia Collaborative Linkage Group for Chromosome 22 . A transmission disequilibrium and linkage analysis of D22S278 marker alleles in 574 families: further support for a susceptibility locus for schizophrenia at 22q12 Schizophr Res 1998 32: 115–121
Kelsoe JR . Loetscher E, Spence MA, Foguet M, Sadovnick AD, Remick RA et al. A genome survey of bipolar disorder indicates a susceptibility locus on chromosome 22 (abstract) Am J Med Genet 1998 81: 461
Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW . Late-onset psychosis in the velo-cardio-facial syndrome (letter) Am J Med Genet 1992 42: 141–142
Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives J Nerv Ment Dis 1994 182: 476–478
Bassett AS, Chow EW . 22q11 deletion syndrome: a genetic subtype of schizophrenia Biol Psychiatry 1999 46: 882–891
Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11 Proc Natl Acad Sci USA 1995 92: 7612–7616
Du Montcel S, Mendizabai H, Ayme S, Levy A, Philip N . Prevalence of 22q11 microdeletion (letter) J Med Genet 1996 33: 719
Devriendt K, Fryns JP, Mortier G, van Thienen MN, Keymolen K . The annual incidence of DiGeorge/velocardiofacial syndrome (letter) J Med Genet 1998 35: 789–790
Lachman HM, Kelsoe JR, Remick RA, Sadovnick AD, Rapaport MH, Lin M et al. DF Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22 Am J Med Genet 1997 74: 121–128
Vincent JB, Paterson AD, Strong E, Petronis A, Kennedy JL . The unstable trinucleotide repeat story of major psychosis Am J Med Genet 2000 97: 77–97
Cummings CJ, Zoghbi HY . Fourteen and counting: unraveling trinucleotide repeat diseases Hum Mol Genet 2000 9: 909–916
Ross CA, Wood JD, Schilling G, Peters MF, Nucifora FC Jr, Cooper JK et al. Polyglutamine pathogenesis Philos Trans R Soc Lond B Biol Sci 1999 354: 1005–1011
Stevanin G, Durr A, Brice A . Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology Eur J Hum Genet 2000 8: 4–18
Bassett AS, Honer WG . Evidence for anticipation in schizophrenia Am J Hum Genet 1994 54: 864–870
Mclnnis MG . Anticipation: an old idea in new genes Am J Hum Genet 1996 59: 973–979
O'Donovan MC, Guy C, Craddock N, Murphy KC, Cardno AG, Jones LA et al. Expanded CAG repeats in schizophrenia and bipolar disorder (letter) Nat Genet 1995 10: 380–381
O'Donovan MC, Guy C, Craddock N, Bowen T, McKeon P, Macedo A et al. Confirmation of association between expanded CAG/CTG repeats and both schizophrenia and bipolar disorder Psychol Med 1996 26: 1145–1153
Morris AG, Gaitonde E, McKenna PJ, Mollon JD, Hunt DM . CAG repeat expansions and schizophrenia: association with disease in females and with early age-at-onset Hum Mol Genet 1995 4: 1957–1961
Petronis A, Bassett AS, Honer WG, Vincent JB, Tatuch Y, Sasaki T et al. Search for unstable DNA in schizophrenia families with evidence for genetic anticipation Am J Hum Genet 1996 59: 905–911
Saleem Q, Vijayakumar M, Mutsuddi M, Chowdhary N, Jain S, Brahmachari SK . Variation at the MJD locus in the major psychoses Am J Med Genet 1998 81: 440–442
Saleem Q, Sreevidya VS, Sudhir J, Vijaya Savithri J, Gowda Y, Rao CB et al. Association analysis of CAG repeats at the KCNN3 locus in Indian patients with bipolar disorder and schizophrenia Am J Med Genet 2000 96: 744–748
Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE et al. The DNA sequence of human chromosome 22 Nature 1999 402: 489–495
McGuffin P, Farmer A, Harvey I . A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system Arch Gen Psychiatry 1991 48: 764–770
Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988 16: 1215
Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS et al. cDNAs with long CAG trinucleotide repeats from human brain Hum Genet 1997 100: 114–122
Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O . Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro DNA Res 2000 7: 273–281
Moriniere S, Saada C, Holbert S, Sidransky E, Galat A, Ginns E et al. Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia? Mol Psychiatry 1999 4: 58–63
Saleem Q, Choudhry S, Mukerji M, Bashyam L, Padma MV, Chakravarthy A et al. Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation Human Genet 2000 106: 107–187
Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD . Do schizophrenia and bipolar disorder share susceptibility genes? Schizophr Res 1999 39: 107–111
Kedra D, Pan H-Q, Seroussi E, Fransson I, Guilbaud C, Collins JE et al. Characterization of the human synaptogyrin gene family Hum Genet 1998 103: 131–141
Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex Neuron 2000 28: 53–67
Stone RL, Aimi J, Barshop BA, Jaeken J, Van den Berghe G, Zalkin H et al. A mutation in adenylosuccinate lyase associated with mental retardation and autistic features Nature Genet 1992 1: 59–63
Acknowledgements
We are grateful to Ms B Sujatha and Dr Vani Brahmachari for providing some of the normal DNA samples, Ms R Jaya and Ms M Ruchi for help with Genescan analysis, Mr Neeraj Pandey for providing primers for the 22CH4 locus, Dr CB Rao and Professor DK Subbukrishna for assistance with statistical analyses. We would like to acknowledge Dr Anuranjan Anand for extraction of patient DNA samples. This work was supported by Dept of Biotechnology, Govt of India and Council of Scientific and Industrial Research, Govt of India.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Saleem, Q., Dash, D., Gandhi, C. et al. Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder. Mol Psychiatry 6, 694–700 (2001). https://doi.org/10.1038/sj.mp.4000924
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4000924
Keywords
This article is cited by
-
Meta-analysis of genomic variants and gene expression data in schizophrenia suggests the potential need for adjunctive therapeutic interventions for neuropsychiatric disorders
Journal of Genetics (2019)
-
Attempts to replicate genetic associations with schizophrenia in a cohort from north India
npj Schizophrenia (2017)
-
Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition
BMC Systems Biology (2011)
-
SYNGR1 is associated with schizophrenia and bipolar disorder in southern India
Journal of Human Genetics (2005)
-
Multicenter linkage study of schizophrenia loci on chromosome 22q
Molecular Psychiatry (2004)