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Variation at the TRIM11 Locus Modifies Progressive Supranuclear Palsy Phenotype

Jabbari, E; Woodside, J; Tan, MMX; Shoai, M; Pittman, A; Ferrari, R; Mok, KY; Zhang, D; Reynolds, RH; de Silva, R; et al. Jabbari, E; Woodside, J; Tan, MMX; Shoai, M; Pittman, A; Ferrari, R; Mok, KY; Zhang, D; Reynolds, RH; de Silva, R; Grimm, M-J; Respondek, G; Müller, U; Al-Sarraj, S; Gentleman, SM; Lees, AJ; Warner, TT; Hardy, J; Revesz, T; Höglinger, GU; Holton, JL; Ryten, M; Morris, HR (2018) Variation at the TRIM11 Locus Modifies Progressive Supranuclear Palsy Phenotype. Ann Neurol, 84 (4). pp. 485-496. ISSN 1531-8249 https://doi.org/10.1002/ana.25308
SGUL Authors: Pittman, Alan Michael

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Abstract

Objective 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. Methods 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. Results 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. Interpretation 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.

Item Type: Article
Additional Information: © 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Ann Neurol
ISSN: 1531-8249
Language: eng
Dates:
DateEvent
16 October 2018Published
9 September 2018Published Online
28 July 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDPSP AssociationUNSPECIFIED
UNSPECIFIEDParkinson's UKUNSPECIFIED
UNSPECIFIEDCytox LimitedUNSPECIFIED
UNSPECIFIEDInnovate UKUNSPECIFIED
UNSPECIFIEDUniversity College London Hospitals Biomedical Research CentreUNSPECIFIED
UNSPECIFIEDAlzheimer's SocietyUNSPECIFIED
UNSPECIFIEDReta Lila Weston TrustUNSPECIFIED
UNSPECIFIEDMedical Research CouncilUNSPECIFIED
UNSPECIFIEDLeonard Wolfson Doctoral Training Fellowship in NeurodegenerationUNSPECIFIED
UNSPECIFIEDCBD SolutionsUNSPECIFIED
PubMed ID: 30066433
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110059
Publisher's version: https://doi.org/10.1002/ana.25308

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