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Molecular Medicine

, Volume 18, Issue 6, pp 1029–1040 | Cite as

Common Variants of the Genes Encoding Erythropoietin and Its Receptor Modulate Cognitive Performance in Schizophrenia

  • Anne Kästner
  • Sabrina Grube
  • Ahmed El-Kordi
  • Beata Stepniak
  • Heidi Friedrichs
  • Derya Sargin
  • Judith Schwitulla
  • Martin Begemann
  • Ina Giegling
  • Kamilla W Miskowiak
  • Swetlana Sperling
  • Kathrin Hannke
  • Anna Ramin
  • Ralf Heinrich
  • Olaf Gefeller
  • Klaus-Armin Nave
  • Dan Rujescu
  • Hannelore Ehrenreich
Research Article

Abstract

Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5′ upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPOR STR(GA)n. Associations of these variants were obtained for cognitive processing speed, fine motor skills and short-term memory readouts, with one particular combination of genotypes superior to all others (p < 0.0001). In an independent healthy control sample (N > 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic expression of constitutively active EPOR in pyramidal neurons of cortex and hippocampus. We thus predicted that the human genotypes associated with better cognition would reflect gain-of-function effects. Indeed, reporter gene assays and quantitative transcriptional analysis of peripheral blood mononuclear cells showed genotype-dependent EPO/EPOR expression differences. Together, these findings reveal a role of endogenous EPO/EPOR for cognition, at least in schizophrenic patients.

Notes

Acknowledgments

This work was supported by the Max Planck Society and the DFG-Research Center for Molecular Physiology of the Brain (CMBP).We thank Fritz Benseler and Anja Ronnenberg for their excellent technical work, and the staff of the animal facility at the Max Planck Institute of Experimental Medicine for maintenance of the mouse colony. We are indebted to all healthy individuals and all patients for their participation in the study, and all collaborating GRAS centers for their support. We are grateful to all colleagues who contributed to the GRAS data collection.

Supplementary material

10020_2012_1861029_MOESM1_ESM.pdf (1.2 mb)
Common Variants of the Genes Encoding Erythropoietin and Its Receptor Modulate Cognitive Performance in Schizophrenia

References

  1. 1.
    Nissenson AR. (1989) Recombinant human erythropoietin: Impact on brain and cognitive function, exercise tolerance, sexual potency, and quality of life. Semin. Nephrol. 9:25–31.PubMedGoogle Scholar
  2. 2.
    Brines M, Cerami A. (2005) Emerging biological roles for erythropoietin in the nervous system. Nat. Rev. Neurosci. 6:484–94.CrossRefGoogle Scholar
  3. 3.
    Sargin D, Friedrichs H, El-Kordi A, Ehrenreich H. (2010) Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research. Best Pract. Res. Clin. Anaesthesiol. 24:573–94.CrossRefGoogle Scholar
  4. 4.
    Siren AL, Fasshauer T, Bartels C, Ehrenreich H. (2009) Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics. 6:108–27.CrossRefGoogle Scholar
  5. 5.
    Adamcio B, et al. (2008) Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol. 6:37.CrossRefGoogle Scholar
  6. 6.
    El-Kordi A, Radyushkin K, Ehrenreich H. (2009) Erythropoietin improves operant conditioning and stability of cognitive performance in mice. BMC Biol. 7:37.CrossRefGoogle Scholar
  7. 7.
    Sargin D, et al. (2011) Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice. BMC Biol. 9:27.CrossRefGoogle Scholar
  8. 8.
    Ehrenreich H, et al. (2007) Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol. Psychiatry. 12:206–20.CrossRefGoogle Scholar
  9. 9.
    Wüstenberg T, et al. (2011) Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol. Psychiatry. 16:26–36, 1.CrossRefGoogle Scholar
  10. 10.
    Miskowiak K, O’Sullivan U, Harmer CJ. (2007) Erythropoietin enhances hippocampal response during memory retrieval in humans. J. Neurosci. 27:2788–92.CrossRefGoogle Scholar
  11. 11.
    Leist M, et al. (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 305:239–42.CrossRefGoogle Scholar
  12. 12.
    Ostrowski D, Ehrenreich H, Heinrich R. (2011) Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro. Neuroscience. 188:95–108.CrossRefGoogle Scholar
  13. 13.
    Iliadou A, et al. (2007) Genomewide scans of red cell indices suggest linkage on chromosome 6q23. J. Med. Genet. 44:24–30.CrossRefGoogle Scholar
  14. 14.
    Lin JP, O’Donnell CJ, Levy D, Cupples LA. (2005) Evidence for a gene influencing haematocrit on chromosome 6q23–24: genomewide scan in the Framingham Heart Study. J. Med. Genet. 42:75–9.CrossRefGoogle Scholar
  15. 15.
    Mejia OM, Prchal JT, Leon-Velarde F, Hurtado A, Stockton DW. (2005) Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. Haematologica. 90:13–9.PubMedGoogle Scholar
  16. 16.
    Percy MJ, McMullin MF, Lappin TR. (1997) Sequence analysis of the 3′ hypoxia-responsive element of the human erythropoietin gene in patients with erythrocytosis. Biochem. Mol. Med. 62:132–4.CrossRefGoogle Scholar
  17. 17.
    Sripichai O. et al. (2005) Genetic analysis of candidate modifier polymorphisms in Hb E-beta 0-thalassemia patients. Ann. N. Y. Acad. Sci. 1054:433–8.CrossRefGoogle Scholar
  18. 18.
    Zeng SM, Yankowitz J, Widness JA, Strauss RG. (2001) Etiology of differences in hematocrit between males and females: sequence-based polymorphisms in erythropoietin and its receptor. J. Gend. Specif. Med. 4:35–40.PubMedGoogle Scholar
  19. 19.
    Sokol L, Prchal J, Prchal JT. (1993) Primary familial and congenital polycythaemia. Lancet. 342:115–6.CrossRefGoogle Scholar
  20. 20.
    Sokol L, Prchal JT. (1994) Two microsatellite repeat polymorphisms in the EPO gene. Hum. Mol. Genet. 3:219.CrossRefGoogle Scholar
  21. 21.
    Balasubbu S, et al. (2010) Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy. BMC Med. Genet. 11:158.CrossRefGoogle Scholar
  22. 22.
    Abhary S, et al. (2010) Association between erythropoietin gene polymorphisms and diabetic retinopathy. Arch. Ophthalmol. 128:102–6.CrossRefGoogle Scholar
  23. 23.
    Tong Z, et al. (2008) Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc. Natl. Acad. Sci. U. S. A. 105:6998–7003.CrossRefGoogle Scholar
  24. 24.
    Ghezzi S, et al. (2009) Is erythropoietin gene a modifier factor in amyotrophic lateral sclerosis? Neurobiol. Aging. 30:842–4.CrossRefGoogle Scholar
  25. 25.
    Begemann M, et al. (2010) Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch. Gen. Psychiatry. 67:879–88.CrossRefGoogle Scholar
  26. 26.
    Ribbe K. et al. (2010) The cross-sectional GRAS sample: a comprehensive phenotypical data collection of schizophrenic patients. BMC Psychiatry. 10:91.CrossRefGoogle Scholar
  27. 27.
    World Medical Association [WMA]. (1964) WMA declaration of Helsinki — ethical principles for medical research involving humans. Last amended 2008 Oct. [cited 2012 Aug 21]. Available from: https://doi.org/www.wma.net/en/30publications/10policies/b3/index.html
  28. 28.
    van den Oord, EJ, et al. (2008) Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Arch. Gen. Psychiatry. 65:1062–71.CrossRefGoogle Scholar
  29. 29.
    Wittchen H-U, Zaudig M, Fydrich T. (1997) SKID-I und SKID-II, Strukturiertes Klinisches Interview für DSM-IV. Hogrefe, Göttingen.Google Scholar
  30. 30.
    Rice JP, et al. (1995) Comparison of direct interview and family history diagnoses of alcohol dependence. Alcohol Clin. Exp. Res. 19:1018–23.CrossRefGoogle Scholar
  31. 31.
    Folstein MF, Folstein SE, McHugh PR. (1975) Mini-Mental State (a practical method for grading the state of patients for the clinician). J. Psych. Res. 12:189–98.CrossRefGoogle Scholar
  32. 32.
    Tewes U. (1994) HAWIE-R. Hamburg-WechslerIntelligenztest für Erwachsene, Revision 1991; Handbuch und Testanweisung. Bern: Verlag Hans Huber.Google Scholar
  33. 33.
    Chapman RL. (1948) The MacQuarrie test for mechanical ability. Psychometrika. 13:175–9.CrossRefGoogle Scholar
  34. 34.
    Helmstaedter C, Durwen HF. (1990) The Verbal Learning and Retention Test. A useful and differentiated tool in evaluating verbal memory performance [in German]. Schweiz. Arch. Neurol. Psychiatr. 141:21–30.PubMedGoogle Scholar
  35. 35.
    Kay SR, Fiszbein A, Opler LA. (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13:261–76.CrossRefGoogle Scholar
  36. 36.
    American Psychiatric Association (APA). (1994) Diagnostic and statistical manual of mental disorders: DSM-IV. 4th edition. Washington (DC): APA.Google Scholar
  37. 37.
    Blom G. (1958) Statistical estimates and transformed beta-variables. Wiley, New York.Google Scholar
  38. 38.
    de la Chapelle A, Sistonen P, Lehvaslaiho H, Ikkala E, Juvonen E. (1993) Familial erythrocytosis genetically linked to erythropoietin receptor gene. Lancet. 341:82–4.CrossRefGoogle Scholar
  39. 39.
    Fandrey J. (2004) Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286:R977–88.CrossRefGoogle Scholar
  40. 40.
    Stockmann C, Fandrey J. (2006) Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clin. Exp. Pharmacol. Physiol. 33:968–79.CrossRefGoogle Scholar
  41. 41.
    Constantinescu SN, et al. (2001) Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc. Natl. Acad. Sci. U. S. A. 98:4379–84.CrossRefGoogle Scholar
  42. 42.
    Yoshimura A, Longmore G, Lodish HF. (1990) Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature. 348:647–9.CrossRefGoogle Scholar
  43. 43.
    Humby T, Wilkinson L, Dawson G. (2005) Assaying aspects of attention and impulse control in mice using the 5-choice serial reaction time task. Curr. Protoc. Neurosci. May 2005:Chapter 8, Unit 8 5H.Google Scholar
  44. 44.
    Robbins TW. (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl.). 163:362–80.CrossRefGoogle Scholar
  45. 45.
    Berger S. (1998) The WAIS-R factors: usefulness and construct validity in neuropsychological assessments. Appl. Neuropsychol. 5:37–42.CrossRefGoogle Scholar
  46. 46.
    Jelkmann W. (2011) Regulation of erythropoietin production. J. Physiol. 589:1251–8.CrossRefGoogle Scholar
  47. 47.
    Wallach I, et al. (2009) Erythropoietin-receptor gene regulation in neuronal cells. Pediatr. Res. 65:619–24.CrossRefGoogle Scholar
  48. 48.
    Assaraf MI, et al. (2007) Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment. J. Neuropathol. Exp. Neurol. 66:389–98.CrossRefGoogle Scholar
  49. 49.
    Ehrenreich H, et al. (2004) Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Mol. Psychiatry. 9:42–54.CrossRefGoogle Scholar
  50. 50.
    Sirén AL, et al. (2001) Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol. 101, 271–6.Google Scholar
  51. 51.
    Ehrenreich H, et al. (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain. 130:2577–88.CrossRefGoogle Scholar
  52. 52.
    Neubauer AP, Voss W, Wachtendorf M, Jungmann T. (2010) Erythropoietin improves neurodevelopmental outcome of extremely preterm infants. Ann. Neurol. 67:657–66.PubMedGoogle Scholar

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Authors and Affiliations

  • Anne Kästner
    • 1
  • Sabrina Grube
    • 1
  • Ahmed El-Kordi
    • 1
    • 7
  • Beata Stepniak
    • 1
  • Heidi Friedrichs
    • 1
  • Derya Sargin
    • 1
  • Judith Schwitulla
    • 2
  • Martin Begemann
    • 1
  • Ina Giegling
    • 3
  • Kamilla W Miskowiak
    • 4
  • Swetlana Sperling
    • 1
  • Kathrin Hannke
    • 1
  • Anna Ramin
    • 1
  • Ralf Heinrich
    • 5
  • Olaf Gefeller
    • 2
  • Klaus-Armin Nave
    • 6
    • 7
  • Dan Rujescu
    • 3
  • Hannelore Ehrenreich
    • 1
    • 7
  1. 1.Division of Clinical NeuroscienceMax Planck Institute of Experimental MedicineGöttingenGermany
  2. 2.Department of Medical Informatics, Biometry, and EpidemiologyUniversity of Erlangen-NürnbergErlangenGermany
  3. 3.Department of PsychiatryLudwig-Maximilian UniversityMunichGermany
  4. 4.Clinic for Affective Disorders, Department of PsychiatryCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  5. 5.Department of Cellular Neurobiology, Institute for ZoologyUniversity of GöttingenGöttingenGermany
  6. 6.Department of NeurogeneticsMax Planck Institute of Experimental MedicineGöttingenGermany
  7. 7.DFG Research Center for Molecular Physiology of the Brain (CMPB)GöttingenGermany

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