Common Variants of the Genes Encoding Erythropoietin and Its Receptor Modulate Cognitive Performance in Schizophrenia
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.
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.
- 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
- 29.Wittchen H-U, Zaudig M, Fydrich T. (1997) SKID-I und SKID-II, Strukturiertes Klinisches Interview für DSM-IV. Hogrefe, Göttingen.Google Scholar
- 32.Tewes U. (1994) HAWIE-R. Hamburg-WechslerIntelligenztest für Erwachsene, Revision 1991; Handbuch und Testanweisung. Bern: Verlag Hans Huber.Google Scholar
- 36.American Psychiatric Association (APA). (1994) Diagnostic and statistical manual of mental disorders: DSM-IV. 4th edition. Washington (DC): APA.Google Scholar
- 37.Blom G. (1958) Statistical estimates and transformed beta-variables. Wiley, New York.Google Scholar
- 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
- 50.Sirén AL, et al. (2001) Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol. 101, 271–6.Google Scholar
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