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 intrinsicrole of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations ofEPO and EPO receptor (EPOR) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) weregenotyped for 5′ upstream–located gene variants, EPO SNP rs1617640 (T/G) and EPOR STR(GA)n. Associations of these variants wereobtained for cognitive processing speed, fine motor skills and short-term memory readouts, with one particular combination ofgenotypes 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 transgenicexpression of constitutively active EPOR in pyramidal neurons of cortex and hippocampus. We thus predicted that thehuman genotypes associated with better cognition would reflect gain-of-function effects. Indeed, reporter gene assays and quantitativetranscriptional 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.