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 Article
  • Published:

Apolipoprotein D is associated with long-term outcome in patients with schizophrenia

The Pharmacogenomics Journal volume 6, pages 120–125 (2006)Cite this article

Abstract

Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second, genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find ApoD alleles, genotypes or haplotypes to be associated with disease. However, we did find that long-term clinical outcome was associated with the ApoD polymorphism rs7659 (P=0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.

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

Similar content being viewed by others

References

  1. Mahadik SP, Evans DR . Is schizophrenia a metabolic brain disorder? Membrane phospholipid dysregulation and its therapeutic implications. Psychiatr Clin N Am 2003; 26: 85–102.

    Article  Google Scholar 

  2. Thomas EA, Copolov DL, Sutcliffe JG . From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders. Curr Mol Med 2003; 3: 408–418.

    Article  CAS  Google Scholar 

  3. Skosnik PD, Yao JK . From membrane phospholipid defects to altered neurotransmission: is arachidonic acid a nexus in the pathophysiology of schizophrenia? Prostaglandins Leukot Essent Fatty Acids 2003; 69: 367–384.

    Article  CAS  Google Scholar 

  4. Lundbaek JA, Andersen OS, Werge T, Nielsen C . Cholesterol-induced protein sorting: an analysis of energetic feasibility. Biophys J 2003; 84: 2080–2089.

    Article  CAS  Google Scholar 

  5. Lundbaek JA, Birn P, Hansen AJ, Sogaard R, Nielsen C, Girshman J et al. Regulation of sodium channel function by bilayer elasticity: the importance of hydrophobic coupling. Effects of Micelle-forming amphiphiles and cholesterol. J Gen Physiol 2004; 123: 599–621.

    Article  CAS  Google Scholar 

  6. Dilley WG, Haagensen DE, Cox CE, Wells Jr SA . Immunologic and steroid binding properties of the GCDFP-24 protein isolated from human breast gross cystic disease fluid. Breast Cancer Res Treat 1990; 16: 253–260.

    Article  CAS  Google Scholar 

  7. Drayna D, Fielding C, McLean J, Baer B, Castro G, Chen E et al. Cloning and expression of human apolipoprotein D cDNA. J Biol Chem 1986; 261: 16535–16539.

    CAS  PubMed  Google Scholar 

  8. Francone OL, Gurakar A, Fielding C . Distribution and functions of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in plasma lipoproteins. Evidence for a functional unit containing these activities together with apolipoproteins A-I and D that catalyzes the esterification and transfer of cell-derived cholesterol. J Biol Chem 1989; 264: 7066–7072.

    CAS  PubMed  Google Scholar 

  9. Simard J, Veilleux R, de Launoit Y, Haagensen DE, Labrie F . Stimulation of apolipoprotein D secretion by steroids coincides with inhibition of cell proliferation in human LNCaP prostate cancer cells. Cancer Res 1991; 51: 4336–4341.

    CAS  PubMed  Google Scholar 

  10. Glenthoej B, Gerlach J, Licht R, Gulmann N, Joergensen O . Clearing rapport no.5 treatment with antispychotics. Recommended guidelines. Klarings rapport no. 5. Behandlings med Antopsykotika. Vejledende retningslinier. Danish Psychiatric Association, 1998.

  11. Morais Cabral JH, Atkins GL, Sanchez LM, Lopez-Boado YS, Lopez-Otin C, Sawyer L . Arachidonic acid binds to apolipoprotein D: implications for the protein's function. FEBS Lett 1995; 366: 53–56.

    Article  CAS  Google Scholar 

  12. Thomas EA, George RC, Sutcliffe JG . Apolipoprotein D modulates arachidonic acid signaling in cultured cells: implications for psychiatric disorders. Prostaglandins Leukot Essent Fatty Acids 2003; 69: 421–427.

    Article  CAS  Google Scholar 

  13. Yao JK, Thomas EA, Reddy RD, Keshavan MS . Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia. Schizophr Res 2005; 72: 259–266.

    Article  Google Scholar 

  14. Rassart E, Bedirian A, Do CS, Guinard O, Sirois J, Terrisse L et al. Apolipoprotein D. Biochim Biophys Acta 2000; 1482: 185–198.

    Article  CAS  Google Scholar 

  15. Yang CY, Gu ZW, Blanco-Vaca F, Gaskell SJ, Yang M, Massey JB et al. Structure of human apolipoprotein D: locations of the intermolecular and intramolecular disulfide links. Biochemistry 1994; 33: 12451–12455.

    Article  CAS  Google Scholar 

  16. Sanchez D, Ganfornina MD, Gutierrez G, Marin A . Exon–intron structure and evolution of the Lipocalin gene family. Mol Biol Evol 2003; 20: 775–783.

    Article  CAS  Google Scholar 

  17. Terrisse L, Poirier J, Bertrand P, Merched A, Visvikis S, Siest G et al. Increased levels of apolipoprotein D in cerebrospinal fluid and hippocampus of Alzheimer's patients. J Neurochem 1998; 71: 1643–1650.

    Article  CAS  Google Scholar 

  18. Navarro A, Del Valle E, Astudillo A, Gonzalez dR, Tolivia J . Immunohistochemical study of distribution of apolipoproteins E and D in human cerebral beta amyloid deposits. Exp Neurol 2003; 184: 697–704.

    Article  CAS  Google Scholar 

  19. Mahadik SP, Khan MM, Evans DR, Parikh VV . Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome. Schizophr Res 2002; 58: 55–62.

    Article  Google Scholar 

  20. Thomas EA, Dean B, Pavey G, Sutcliffe JG . Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: implications for the pathophysiology of psychiatric disorders. Proc Natl Acad Sci USA 2001; 98: 4066–4071.

    Article  CAS  Google Scholar 

  21. Mancama D, Arranz MJ, Kerwin RW . Genetic predictors of therapeutic response to clozapine: current status of research. CNS Drugs 2002; 16: 317–324.

    Article  CAS  Google Scholar 

  22. Masellis M, Basile VS, Ozdemir V, Meltzer HY, Macciardi FM, Kennedy JL . Pharmacogenetics of antipsychotic treatment: lessons learned from clozapine. Biol Psychiatry 2000; 47: 252–266.

    Article  CAS  Google Scholar 

  23. Thomas EA, Danielson PE, Nelson PA, Pribyl TM, Hilbush BS, Hasel KW et al. Clozapine increases apolipoprotein D expression in rodent brain: towards a mechanism for neuroleptic pharmacotherapy. J Neurochem 2001; 76: 789–796.

    Article  CAS  Google Scholar 

  24. Khan MM, Parikh VV, Mahadik SP . Antipsychotic drugs differentially modulate apolipoprotein D in rat brain. J Neurochem 2003; 86: 1089–1100.

    Article  CAS  Google Scholar 

  25. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  Google Scholar 

  26. Desai PP, Hendrie HC, Evans RM, Murrell JR, DeKosky ST, Kamboh MI . Genetic variation in apolipoprotein D affects the risk of Alzheimer disease in African-Americans. Am J Med Genet 2003; 116B: 98–101.

    Article  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. Jakobsen KD, Frederiksen JN, Hansen T, Jansson LB, Parnas J, Werge T . Reliability of clinical ICD-10 schizophrenia diagnoses. Nordic J Psychiatry 2005; 59: 209–212.

    Article  Google Scholar 

  29. Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A et al. The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl 2003; 416: 16–23.

    Article  Google Scholar 

  30. American Psychiatric Association. Treatment Guidelines. www.Psych Org/Psych_Pract/Treatg/ 2005.

  31. Meltzer HY, Rabinowitz J, Lee MA, Cola PA, Ranjan R, Findling RL et al. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry 1997; 154: 475–482.

    Article  CAS  Google Scholar 

  32. Liu HX, Chew SL, Cartegni L, Zhang MQ, Krainer AR . Exonic splicing enhancer motif recognized by human SC35 under splicing conditions. Mol Cell Biol 2000; 20: 1063–1071.

    Article  CAS  Google Scholar 

  33. Tregouet DA, Escolano S, Tiret L, Mallet A, Golmard JL . A new algorithm for haplotype-based association analysis: the stochastic-EM algorithm. Ann Hum Genet 2004; 68 (Part 2): 165–177.

    Article  CAS  Google Scholar 

  34. Wittke-Thompson JK, Pluzhnikov A, Cox NJ . Rational inferences about departures from Hardy–Weinberg equilibrium. Am J Hum Genet 2005; 76: 967–986.

    Article  CAS  Google Scholar 

  35. Packer BR, Yeager M, Staats B, Welch R, Crenshaw A, Kiley M et al. SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes. Nucleic Acids Res 2004; 32: D528–D532.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank patients who participated in the Danish Psychiatric Biobank and made this study possible. We also acknowledge the help of numerous mental health professionals in the various clinical departments and research technicians. This study was financed through grant to TW from the Danish Research Agency under the Center for Pharmacogenomics and the Danish Psychiatric Research Foundation.

Author information

Authors and Affiliations

  1. Research Institute of Biological Psychiatry, Copenhagen University Hospital, H:S Sct. Hans Hospital, Roskilde, Denmark

    T Hansen, L Olsen, K Søeby, K D Jakobsen, H B Rasmussen & T Werge

  2. University Department of Psychiatry, H:S Bispebjerg Hospital, København NV, Denmark

    R P Hemmingsen

  3. Faculty of Medicine, University of Copenhagen, København N, Denmark

    R P Hemmingsen

  4. University Department of Psychiatry, H:S Amager Hospital, København S, Denmark

    A G Wang

  5. University Department of Psychiatry, H:S Frederiksberg Hospital, Frederiksberg, Denmark

    S Timm

  6. University Department of Clinical Biochemistry, H:S Hvidovre Hospital, Hvidovre, Denmark

    M Fenger

  7. University Department of Psychiatry, H:S Hvidovre Hospital, Hvidovre, Denmark

    J Parnas

Authors
  1. T Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R P Hemmingsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A G Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Olsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Timm
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Søeby
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K D Jakobsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Fenger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Parnas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H B Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T Werge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Werge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hansen, T., Hemmingsen, R., Wang, A. et al. Apolipoprotein D is associated with long-term outcome in patients with schizophrenia. Pharmacogenomics J 6, 120–125 (2006). https://doi.org/10.1038/sj.tpj.6500350

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500350

Keywords

This article is cited by

Search

Advanced search

Quick links