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Genome wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

ABSTRACT: We conducted GWAS of sporadic CJD, variant CJD, iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen), for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses.

PROVIDER: EGAS00000000097 | EGA |

REPOSITORIES: EGA

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Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.

Mead Simon S Uphill James J Beck John J Poulter Mark M Campbell Tracy T Lowe Jessica J Adamson Gary G Hummerich Holger H Klopp Norman N Rückert Ina-Maria IM Wichmann H-Erich HE Azazi Dhoyazan D Plagnol Vincent V Pako Wandagi H WH Whitfield Jerome J Alpers Michael P MP Whittaker John J Balding David J DJ Zerr Inga I Kretzschmar Hans H Collinge John J

Human molecular genetics 20111230 8

Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru an ...[more]

PMID: 22210626

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Project description:Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared messenger RNA (mRNA) expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE was distinct from that found in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. We also found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

Dataset Information

Genome wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

Publications

Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.

Similar Datasets

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