Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype

摘要: Objective: The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) identify genetic determinants of PSP phenotype. Methods: Two independent pathological and clinically diagnosed cohorts were genotyped phenotyped create Richardsons syndrome (RS) non-RS groups. carried out separate logistic regression GWAS compare RS groups then combined datasets carry whole cohort analysis (n=497). validated our findings in third by referring data from 100 deeply cases the original case-control GWAS. assessed expression/co-expression patterns identified genes used gene-based testing. Results: Our lead single nucleotide polymorphism (SNP), rs564309, showed an signal both cohorts, reaching significance analysis: OR 5.55, p value 1.7x10-9. rs564309 intronic variant tripartite motif-containing protein 11 (TRIM11) gene, component ubiquitin proteasome system (UPS). In cohort, minor allele frequencies surrogate SNPs high LD with replicated findings. Gene based testing confirmed at TRIM11. found that TRIM11 predominantly expressed neurons cerebellum basal ganglia. Interpretation: suggests locus modifier phenotype potentially adds further evidence UPS having key role tau pathology, therefore representing target disease modifying therapies.