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Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.
- Source :
-
Annals of Neurology . Oct2018, Vol. 84 Issue 4, p485-496. 12p. - Publication Year :
- 2018
-
Abstract
- <bold>Objective: </bold>The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome-wide association study (GWAS) to identify genetic determinants of PSP phenotype.<bold>Methods: </bold>Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non-RS groups. We carried out separate logistic regression GWASs to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non-RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene-based association testing.<bold>Results: </bold>Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome-wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2-10.0, p = 1.7 × 10-9 ). rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene-based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.<bold>Interpretation: </bold>Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease-modifying therapies. Ann Neurol 2018;84:485-496. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03645134
- Volume :
- 84
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Annals of Neurology
- Publication Type :
- Academic Journal
- Accession number :
- 132423231
- Full Text :
- https://doi.org/10.1002/ana.25308