RESUMO
Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic.
Assuntos
Corpo Estriado/efeitos dos fármacos , Haloperidol/metabolismo , Esquizofrenia/genética , Animais , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Haloperidol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco , Psicologia do Esquizofrênico , Análise de Sequência de RNARESUMO
Sixteen microsatellite markers, including two described here, were used to construct a high-resolution map of the 1q32 region encompassing the regulator of the complement activation (RCA) gene cluster. The RCA genes are a group of related genes coding for plasma and membrane associated proteins that collectively control activation of the complement component C3. We provide here the location of two new genes within the RCA gene cluster. These genes are PFKFB2 that maps 15 kilobases (kb) upstream of the C4BPB gene, and a gene located 4 kb downstream of C4BPA, which seems to code for the 72 000 Mr component of the signal recognition particle (SRP72). Neither of these two genes is related structurally or functionally to the RCA genes. In addition, our map shows the centromere-telomere orientation of the C4BPB/MCP linkage group, which is: centromere-PFKFB2-C4BPB-C4BPA-SRP72-C4BPAL1++ +-C4BPAL2-telomere, and outlines an interval with a significant female-male recombination difference which suggests the presence of a female-specific hotspot(s) of recombination.
