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

doi:10.2119/molmed.2012.00190

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

25 Citations (Scopus)

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 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.

Original language	English
Journal	Molecular medicine (Cambridge, Mass.)
Volume	18
Pages (from-to)	1029-40
Number of pages	12
ISSN	1076-1551
DOIs	https://doi.org/10.2119/molmed.2012.00190
Publication status	Published - 7 Sept 2012

Keywords

Adolescent
Adult
Aged
Animals
Case-Control Studies
Cerebral Cortex
Cognition
Demography
Erythropoietin
Female
Genetic Association Studies
Genetic Predisposition to Disease
Hippocampus
Humans
Male
Memory
Mice
Middle Aged
Neurons
Phenotype
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Pyramidal Cells
Receptors, Erythropoietin
Schizophrenia
Young Adult
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2119/molmed.2012.00190Licence: CC BY

pmc3459483?pdf=renderFinal published version, 918 KB

Cite this

Kästner, A., Grube, S., El-Kordi, A., Stepniak, B., Friedrichs, H., Sargin, D., Schwitulla, J., Begemann, M., Giegling, I., Miskowiak, K. W., Sperling, S., Hannke, K., Ramin, A., Heinrich, R., Gefeller, O., Nave, K-A., Rujescu, D., & Ehrenreich, H. (2012). Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia. Molecular medicine (Cambridge, Mass.), 18, 1029-40. https://doi.org/10.2119/molmed.2012.00190

Kästner, A, Grube, S, El-Kordi, A, Stepniak, B, Friedrichs, H, Sargin, D, Schwitulla, J, Begemann, M, Giegling, I, Miskowiak, KW, Sperling, S, Hannke, K, Ramin, A, Heinrich, R, Gefeller, O, Nave, K-A, Rujescu, D & Ehrenreich, H 2012, 'Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia', Molecular medicine (Cambridge, Mass.), vol. 18, pp. 1029-40. https://doi.org/10.2119/molmed.2012.00190

@article{c6561d0bacb74a9fbd17a755376a372d,

title = "Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia",

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 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.",

keywords = "Adolescent, Adult, Aged, Animals, Case-Control Studies, Cerebral Cortex, Cognition, Demography, Erythropoietin, Female, Genetic Association Studies, Genetic Predisposition to Disease, Hippocampus, Humans, Male, Memory, Mice, Middle Aged, Neurons, Phenotype, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Pyramidal Cells, Receptors, Erythropoietin, Schizophrenia, Young Adult, Journal Article, Research Support, Non-U.S. Gov't",

author = "Anne K{\"a}stner and Sabrina Grube and Ahmed El-Kordi and Beata Stepniak and Heidi Friedrichs and Derya Sargin and Judith Schwitulla and Martin Begemann and Ina Giegling and Miskowiak, {Kamilla W} and Swetlana Sperling and Kathrin Hannke and Anna Ramin and Ralf Heinrich and Olaf Gefeller and Klaus-Armin Nave and Dan Rujescu and Hannelore Ehrenreich",

year = "2012",

month = sep,

day = "7",

doi = "10.2119/molmed.2012.00190",

language = "English",

volume = "18",

pages = "1029--40",

journal = "Molecular Medicine",

issn = "1076-1551",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

AU - Kästner, Anne

AU - Grube, Sabrina

AU - El-Kordi, Ahmed

AU - Stepniak, Beata

AU - Friedrichs, Heidi

AU - Sargin, Derya

AU - Schwitulla, Judith

AU - Begemann, Martin

AU - Giegling, Ina

AU - Miskowiak, Kamilla W

AU - Sperling, Swetlana

AU - Hannke, Kathrin

AU - Ramin, Anna

AU - Heinrich, Ralf

AU - Gefeller, Olaf

AU - Nave, Klaus-Armin

AU - Rujescu, Dan

AU - Ehrenreich, Hannelore

PY - 2012/9/7

Y1 - 2012/9/7

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Animals

KW - Case-Control Studies

KW - Cerebral Cortex

KW - Cognition

KW - Demography

KW - Erythropoietin

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Hippocampus

KW - Humans

KW - Male

KW - Memory

KW - Mice

KW - Middle Aged

KW - Neurons

KW - Phenotype

KW - Polymorphism, Genetic

KW - Polymorphism, Single Nucleotide

KW - Pyramidal Cells

KW - Receptors, Erythropoietin

KW - Schizophrenia

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.2119/molmed.2012.00190

DO - 10.2119/molmed.2012.00190

M3 - Journal article

C2 - 22669473

SN - 1076-1551

VL - 18

SP - 1029

EP - 1040

JO - Molecular Medicine

JF - Molecular Medicine

ER -

Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this