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What Can We Learn from Late-Onset Schizophrenia? Comprehensive Genomic and Clinical Characterization of Late-Onset versus Normal- and Early-Onset Cases (LOSzGenPhen)
Date du début: 1 mars 2014, Date de fin: 28 févr. 2017 PROJET  TERMINÉ 

Schizophrenia (SZ) is a debilitating disorder affecting 1% of the population and shows a strong genetic component. Onset of SZ is usually before age 40, but 1.2% have onset after 40. These individuals show marked differences from earlier onset, including more female cases, improved cognition, and more paranoid symptoms. The burden of late-onset SZ (LOS) is likely to grow due to the ageing population in Europe. However, little research has been conducted on LOS and the genomics of LOS have not been examined.Recent technological breakthroughs have allowed the interrogation of the genome to uncover the genetic underpinnings of SZ, and genome-wide association studies (GWAS) have been successful at finding replicated associated markers. To date, studies have not examined genetic differences between LOS and earlier onset cases. The proposed study will be the largest to examine clinical and genetic correlates of LOS vs normal onset (NOS; 18-39 yrs) and vs early onset (EOS; <18 yrs), with 400 LOS and 25,000 N/EOS.Utilising WTCCC2 GWAS data (50 LOS), the minor allele of a single nucleotide polymorphism (SNP) in the gene PREX2 was GWAS-significantly more frequent in LOS vs NOS cases and this association was replicated in an independent GWAS (79 LOS). In both GWAS, the minor allele was most frequent in LOS (10-13%), intermediate in NOS (2-4%) and lowest in EOS (1-2%), suggesting a protective effect against earlier development of SZ. In controls, the frequency of the minor allele was 4-6%, indicating it was not conferring LOS-specific risk. PREX2 is part of the RAC1 pathway containing several SZ candidate genes and GWAS support association of PREX2 with working memory and processing speed. A knockout mouse model has shown SZ-related phenotypes.Identification of genetic factors protective against developing SZ may help to develop drug targets to prevent onset. If successful, funding will help me integrate fully into TCD by providing me with the framework for a major grant.