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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.

SUBMITTER: Kastner A

PROVIDER: S-EPMC3459483 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Kästner Anne A Grube Sabrina S El-Kordi Ahmed A Stepniak Beata B Friedrichs Heidi H Sargin Derya D Schwitulla Judith J Begemann Martin M Giegling Ina I Miskowiak Kamilla W KW Sperling Swetlana S Hannke Kathrin K Ramin Anna A Heinrich Ralf R Gefeller Olaf O Nave Klaus-Armin KA Rujescu Dan D Ehrenreich Hannelore H

Molecular medicine (Cambridge, Mass.) 20120907

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 o ...[more]

PMID: 22669473

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Project description:BackgroundThere is an established association between type 2 diabetes and accelerated cognitive decline. The exact mechanism linking type 2 diabetes and reduced cognitive function is less clear. The monoamine system, which is extensively involved in cognition, can be altered by type 2 diabetes status. Thus, this study hypothesized that sequence variants in genes linked to dopamine metabolism and associated pathways are associated with cognitive function as assessed by the Digit Symbol Substitution Task, the Modified Mini-Mental State Examination, the Stroop Task, the Rey Auditory-Verbal Learning Task, and the Controlled Oral Word Association Task for Phonemic and Semantic Fluency in the Diabetes Heart Study, a type 2 diabetes-enriched familial cohort (n = 893).MethodsTo determine the effects of candidate variants on cognitive performance, genetic association analyses were performed on the well-documented variable number tandem repeat located in the 3' untranslated region of the dopamine transporter, as well as on single-nucleotide polymorphisms covering genes in the dopaminergic pathway, the insulin signaling pathway, and the convergence of both. Next, polymorphisms in loci of interest with strong evidence for involvement in dopamine processing were extracted from genetic datasets available in a subset of the cohort (n = 572) derived from Affymetrix(®) Genome-Wide Human SNP Array 5.0 and 1000 Genomes imputation from this array.ResultsThe candidate gene analysis revealed one variant from the DOPA decarboxylase gene, rs10499695, to be associated with poorer performance on a subset of Rey Auditory-Verbal Learning Task measuring retroactive interference (P = 0.001, β = -0.45). Secondary analysis of genome-wide and imputed data uncovered another DOPA decarboxylase variant, rs62445903, also associated with retroactive interference (P = 7.21 × 10(-7), β = 0.3). These data suggest a role for dopaminergic genes, specifically a gene involved in regulation of dopamine synthesis, in cognitive performance in type 2 diabetes.

Dataset Information

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

Publications

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

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