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.

  • Original Research Article
  • Published:

Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples

Molecular Psychiatry volume 6, pages 202–210 (2001)Cite this article

Abstract

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. we determined its genomic structure and detected three new single nucleotide polymorphisms (snps). in the present study, we screened the gene further to search for additional polymorphisms in japanese samples and identified seven other snps, including a novel missense mutation. these polymorphisms clustered into three regions of the gene. three relatively informative snps, 58g>a, ivs1–15g>a and 800c>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031–0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 Proc Natl Acad Sci USA 1999 96: 5604–5609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD . Do schizophrenia and affective disorder share susceptibility genes? Schizophrenia Res 1999 39: 107–111

    Article  CAS  Google Scholar 

  3. Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr et al. Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene Proc Natl Acad Sci USA 1994 91: 5918–5921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect Am J Hum Genet 1995 57: 1384–1394

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Nöthen MM, Cichon S, Rohleder H, Hemmer S, Franzek E, Fritze J et al. Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families Mol Psychiatry 1999 4: 76–84

    Article  PubMed  Google Scholar 

  6. Schwab SG, Hallmayer J, Lerer B, Albus M, Borrmann M, Honig S et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis Am J Hum Genet 1998 63: 1139–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yoshikawa T, Sanders AR, Esterling LE, Overhauser J, Garnes JA, Lennon G et al. Isolation of chromosome 18-specific brain transcripts as positional candidates for bipolar disorder Am J Med Genet 1997 74: 140–149

    Article  CAS  PubMed  Google Scholar 

  8. Yoshikawa T, Turner G, Esterling LE, Sanders AR, Detera-Wadleigh SD . A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder Mol Psychiatry 1997 2: 393–397

    Article  CAS  PubMed  Google Scholar 

  9. Atack JR . Inositol monophosphatase, the putative therapeutic target for lithium Brain Res Rev 1996 22: 183–190

    Article  CAS  PubMed  Google Scholar 

  10. Shimon H, Sobolev Y, Davidson M, Haroutunian V, Belmaker RH, Agam G . Inositol levels are decreased in postmortem brain of schizophrenic patients Biol Psychiatry 1998 44: 428–432

    Article  CAS  PubMed  Google Scholar 

  11. Yoshikawa T, Padigaru M, Karkera JD, Sharma M, Berrettini WH, Esterling LE et al. Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2) Mol Psychiatry 2000 5: 165–171

    Article  CAS  PubMed  Google Scholar 

  12. Berrettini WH, Goldin LR, Martinez MM, Maxwell ME, Smith AL, Guroff JJ et al. A bipolar pedigree series for genomic mapping of disease genes: diagnostic and analytic considerations Psychiatr Genet 1991 2: 125–160

    Article  Google Scholar 

  13. Toyota T, Watanabe A, Shibuya H, Nankai M, Hattori E, Yamada Kurumaji A et al. Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler Mol Psychiatry 2000 5: 489–494

    Article  CAS  PubMed  Google Scholar 

  14. Sham PC, Curtis D . Monte-Carlo tests for association between disease and alleles at highly polymorphic loci Ann Hum Genet 1995 59: 97–105

    Article  CAS  PubMed  Google Scholar 

  15. Armitage P . Test for linear trend in proportions and frequencies Biometrics 1955 11: 375–386

    Article  Google Scholar 

  16. Schneider S, Kueffer J-M, Roessli D, Excoffier L . Arlequin ver. 1.1: a software for population genetic data analysis Genetics and Biometry Laboratory, University of Geneva, Switzerland

  17. Sjoholt G, Gulbrandsen AK, Lovlie R, Berle JO, Molven A, Steen VM . A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients Mol Psychiatry 2000 5: 172–180

    Article  CAS  PubMed  Google Scholar 

  18. Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R et al. Mechanism of inositol monophosphatase, the putative target of lithium therapy Proc Natl Acad Sci USA 1994 91: 5766–5770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cohen J . Statistical Power Analysis for the Behavioral Sciences, 2nd edn Lawrence Erlbaum Associates: New Jersey 1988

    Google Scholar 

  20. Martin ER, Gilbert JR, Lai EH, Riley J, Rogala AR, Slotterbeck BD et al. Analysis of association at single nucleotide polymorphisms in the APOE region Genomics 2000 63: 7–12

    Article  CAS  PubMed  Google Scholar 

  21. Collins A, Lonjou C, Morton NE . Genetic epidemiology of single-nucleotide polymorphisms Proc Natl Acad Sci USA 1999 96: 15173–15177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ott J . Predicting the range of linkage disequilibrium Proc Natl Acad Sci USA 2000 97: 2–3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by (1) the Research Grant (9B-5) for Nervous and Mental Disorders from the Ministry of Health and Welfare of Japan, (2) Grant-in-Aid for Scientific Research (C), Ministry of Education, Japan (No. 10670891), and (3) RIKEN BSI Grant 637–57731. We thank Dr Arinami for his help on the statistical issues and Dr Alejandro Schaffer for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Laboratory for Molecular Psychiatry, Brain Science Institute, RIKEN, Wako, 351–0198, Saitama, Japan

    T Yoshikawa, M Kikuchi, K Saito, A Watanabe, K Yamada & E Hattori

  2. Department of Neuropsychiatry, Tokyo Medical and Dental University, Tokyo, Japan

    M Kikuchi, A Watanabe, A Kurumaji, H Ishiguro, Y Okubo & M Toru

  3. National Sanatorium Minami-Hanamaki Hospital, Iwate, Japan

    H Shibuya & E Hattori

  4. Department of Neuropsychiatry, Tokyo Metropolitan Police Hospital, Japan

    M Nankai

  5. Department of Neuropsychiatry, Hokushin General Hospital, Nagano, Japan

    H Shimizu

  6. National Institute of Mental Health Intramural Program, National Institutes of Health, Bethesda, 20892-4094, MD, USA

    S D Detera-Wadleigh

Authors
  1. T Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Shibuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Nankai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Kurumaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H Ishiguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y Okubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Toru
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S D Detera-Wadleigh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Yoshikawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshikawa, T., Kikuchi, M., Saito, K. et al. Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples. Mol Psychiatry 6, 202–210 (2001). https://doi.org/10.1038/sj.mp.4000835

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000835

Keywords

This article is cited by

Search

Advanced search

Quick links