Jabbari, Edwin, Woodside, John, Tan, Manuela MX, Shoai, Maryam, Pittman, Alan, Ferrari, Raffaele, Mok, Kin Y, Zhang, David, Reynolds, Regina H, de Silva, Rohan et al (show 13 more authors)
(2018)
Variation at the <i>TRIM11</i> locus modifies progressive supranuclear palsy phenotype.
ANNALS OF NEUROLOGY, 84 (4).
pp. 485-496.
Abstract
<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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<sup>-9</sup> ). 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.<h4>Interpretation</h4>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.
Item Type: | Article |
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Additional Information: | publicationstatus: online-published |
Uncontrolled Keywords: | Humans, Supranuclear Palsy, Progressive, Ubiquitin-Protein Ligases, Case-Control Studies, Cohort Studies, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genetic Variation, Genetic Loci, Tripartite Motif Proteins |
Depositing User: | Symplectic Admin |
Date Deposited: | 18 Feb 2019 10:42 |
Last Modified: | 14 Oct 2023 11:21 |
DOI: | 10.1002/ana.25308 |
Open Access URL: | http://doi.org/10.1002/ana.25308 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3032900 |