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 EPORSTR(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.
Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
Anne
A
Kästner
Sabrina
S
Grube
Ahmed
A
El-Kordi
Beata
B
Stepniak
Heidi
H
Friedrichs
Derya
D
Sargin
Judith
J
Schwitulla
Martin
M
Begemann
Ina
I
Giegling
Kamilla W
KW
Miskowiak
Swetlana
S
Sperling
Kathrin
K
Hannke
Anna
A
Ramin
Ralf
R
Heinrich
Olaf
O
Gefeller
Klaus-Armin
KA
Nave
Dan
D
Rujescu
Hannelore
H
Ehrenreich
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D003071:Cognition; D003710:Demography; D004921:Erythropoietin / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008568:Memory; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D017467:Receptors, Erythropoietin / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
D017467:Receptors, Erythropoietin; D004921:Erythropoietin