Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3

Molecular Psychiatry volume 11, pages 134–142 (2006)Cite this article

Abstract

Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. To fine map this locus we carried out tests of allelic association using 30 genetic markers near the telomere at 21q22.3 in 600 bipolar research subjects and 450 ancestrally matched supernormal control subjects. We found significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Blackwood DH, Visscher PM, Muir WJ . Genetic studies of bipolar affective disorder in large families. Br J Psychiatry Suppl 2001; 41: s134–s136.

    Article  CAS  Google Scholar 

  2. Craddock N, Jones I . Molecular genetics of bipolar disorder. Br J Psychiatry 2001; 178: S128–S133.

    Article  CAS  Google Scholar 

  3. Rifkin L, Gurling H . Genetic aspects of affective disorders. In: Horton R, Katona C (eds). Biological Aspects of Affective Disorders. Academic Press: London, 1991, pp. 305–329.

    Chapter  Google Scholar 

  4. Straub R, Lehner T, Luo Y, Loth J, Shao W, Sharpe L et al. A possible vulnerability locus for bipolar affective-disorder on chromosome 21q22.3. Nat Genet 1994; 8: 291–296.

    Article  CAS  Google Scholar 

  5. Aita V, Liu J, Knowles J, Terwilliger J, Baltazar R, Grunn A et al. A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Am J Hum Genet 1999; 64: 210–217.

    Article  CAS  Google Scholar 

  6. Liu J, Juo SH, Terwilliger JD, Grunn A, Tong X, Brito M et al. A follow-up linkage study supports evidence for a bipolar affective disorder locus on chromosome 21q22. Am J Med Genet 2001; 105: 189–194.

    Article  CAS  Google Scholar 

  7. LaBuda MC, Maldonado M, Marshall D, Otten K, Gerhard DS . A follow-up report of a genome search for affective disorder predisposition loci in the Old Order Amish. Am J Hum Genet 1996; 59: 1343–1362.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. DeteraWadleigh S, Badner J, Goldin L, Berrettini W, Sanders A, Rollins D et al. Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q. Am J Hum Genet 1996; 58: 1279–1285.

    CAS  Google Scholar 

  9. Vallada H, Craddock N, Vasques L, Curtis D, Kirov G, Lauriano V et al. Linkage studies in bipolar affective disorder with markers on chromosome 21. J Affect Disord 1996; 41: 217–221.

    Article  CAS  Google Scholar 

  10. Smyth C, Kalsi G, Curtis D, Brynjolfsson J, Oneill J, Rifkin L et al. Two-locus admixture linkage analysis of bipolar and unipolar affective disorder supports the presence of susceptibility loci on chromosomes 11p15 and 21q22. Genomics 1997; 39: 271–278.

    Article  CAS  Google Scholar 

  11. DeteraWadleigh SD, Badner JA, Yoshikawa T, Sanders AR, Goldin LR, Turner G et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q. Am J Med Genet 1997; 74: 254–262.

    Article  CAS  Google Scholar 

  12. Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B et al. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23–q24. Am J Med Genet 1999; 88: 567–587.

    Article  CAS  Google Scholar 

  13. Kwok JB, Adams LJ, Salmon JA, Donald JA, Mitchell PB, Schofield PR . Nonparametric simulation-based statistical analyses for bipolar affective disorder locus on chromosome 21q22.3. Am J Med Genet 1999; 88: 99–102.

    Article  CAS  Google Scholar 

  14. Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA et al. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 2001; 98: 585–590.

    Article  CAS  Google Scholar 

  15. Ewald H, Kruse TA, Mors O . Genome wide scan using homozygosity mapping and linkage analyses of a single pedigree with affective disorder suggests oligogenic inheritance. Am J Med Genet 2003; 120B: 63–71.

    Article  Google Scholar 

  16. Gurling H . Chromosome 21 workshop. Psychiatr Genet 1998; 8: 109–113.

    Article  CAS  Google Scholar 

  17. Spitzer R, Endicott J . The Schedule for Affective Disorders and Schizophrenia, Lifetime Version, 3rd edn, New York State Psychiatric Institute: New York, 1977.

    Google Scholar 

  18. Spitzer R, Endicott J, Robins E . Research Diagnostic Criteria for a Selected Group of Functional Disorders, 3rd edn, New York State Psychiatric Institute: New York, 1978.

    Google Scholar 

  19. Sambrook J, Fritsch EF, Maniatis T . Molecular Cloning: A Laboratory Manual, 2nd edn, Cold Spring Harbor Laboratory Press: New York, 1989.

    Google Scholar 

  20. Scott HS, Kyriakou DS, Peterson P, Heino M, Tahtinen M, Krohn K et al. Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis. Genomics 1998; 47: 64–70.

    Article  CAS  Google Scholar 

  21. Sham P, Curtis D . Monte-Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: 97–105.

    Article  CAS  Google Scholar 

  22. Zhao JH, Lissarrague S, Essioux L, Sham PC . GENECOUNTING: haplotype analysis with missing genotypes. Bioinformatics 2002; 18: 1694–1695.

    Article  CAS  Google Scholar 

  23. Curtis D, Knight J, Sham PC . Program report: GENECOUNTING support programs. Ann Hum Genet 2005; doi:10.1111/j.1529-8817.2005.00225.x.

  24. Kirov G, Lowry CA, Stephens M, Oldfield S, O'Donovan MC, Lightman SL et al. Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder. Mol Psychiatry 2001; 6: 671–677.

    Article  CAS  Google Scholar 

  25. Saito T, Guan F, Papolos DF, Lau S, Klein M, Fann CS et al. Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. Mol Psychiatry 2001; 6: 387–395.

    Article  CAS  Google Scholar 

  26. Nakamura M, Ueno S, Sano A, Tanabe H . Polymorphisms of the human homologue of the Drosophila white gene are associated with mood and panic disorders. Mol Psychiatry 1999; 4: 155–162.

    Article  CAS  Google Scholar 

  27. Nagamine K, Kudoh J, Minoshima S, Kawasaki K, Asakawa S, Ito F et al. Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 1998; 54: 124–131.

    Article  CAS  Google Scholar 

  28. Yoon IS, Li PP, Siu KP, Kennedy JL, Macciardi F, Cooke RG et al. Altered TRPC7 gene expression in bipolar-I disorder. Biol Psychiatry 2001; 50: 620–626.

    Article  CAS  Google Scholar 

  29. Zhang W, Chu X, Tong Q, Cheung JY, Conrad K, Masker K et al. A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J Biol Chem 2003; 278: 16222–16229.

    Article  CAS  Google Scholar 

  30. Uemura T, Kudoh J, Noda S, Kanba S, Shimizu N . Characterization of human and mouse TRPM2 genes: identification of a novel N-terminal truncated protein specifically expressed in human striatum. Biochem Biophys Res Commun 2005; 328: 1232–1243.

    Article  CAS  Google Scholar 

  31. Wehage E, Eisfeld J, Heiner I, Jungling E, Zitt C, Luckhoff A . Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem 2002; 277: 23150–23156.

    Article  CAS  Google Scholar 

  32. Scheel H, Tomiuk S, Hofmann K . A common protein interaction domain links two recently identified epilepsy genes. Hum Mol Genet 2002; 11: 1757–1762.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The research was funded by Medical Research Council grant G9623693N and by a research lectureship from the Priory Hospital, London to Dr J Lawrence and by the Neuroscience Research Charitable Trust. We thank London IDEAS Genetics Knowledge Park for the use of their Pyrosequencing genotyping facility. We also acknowledge the help of Hamish Scott and Stylianos Antonarakis for providing unpublished mapping information and primer sequences.

Author information

Authors and Affiliations

  1. Department of Mental Health Sciences, Molecular Psychiatry Laboratory, Royal Free and University College London Medical School, Windeyer Institute of Medical Sciences, London, UK

    A McQuillin, N J Bass, G Kalsi, J Lawrence, V Puri, K Choudhury & H M D Gurling

  2. Genetic Basis for Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD, USA

    S D Detera-Wadleigh

  3. Department of Psychological Medicine, St Bartholomew's and Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, London, UK

    D Curtis

Authors
  1. A McQuillin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N J Bass
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Kalsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V Puri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S D Detera-Wadleigh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Curtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H M D Gurling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H M D Gurling.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

McQuillin, A., Bass, N., Kalsi, G. et al. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. Mol Psychiatry 11, 134–142 (2006). https://doi.org/10.1038/sj.mp.4001759

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001759

Keywords

  • chromosome 21
  • manic depression
  • linkage disequilibrium
  • genetic susceptibility

This article is cited by

Search

Advanced search

Quick links