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Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype

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Title: Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype
Authors: Jabbari, E
Woodside, J
Tan, M
Shoai, M
Pittman, A
Ferrari, R
Mok, KY
Zhang, D
Reynolds, RH
De Silva, R
Grimm, MJ
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
Item Type: Journal Article
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's syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS 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/co-expression 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 - OR 5.5 (3.2-10.0), p-value 1.7x10-9 . 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. This article is protected by copyright. All rights reserved.
Issue Date: 31-Jul-2018
Date of Acceptance: 28-Jul-2018
URI: http://hdl.handle.net/10044/1/61961
DOI: https://dx.doi.org/10.1002/ana.25308
ISSN: 0364-5134
Publisher: Wiley
Start Page: 485
End Page: 496
Journal / Book Title: Annals of Neurology
Volume: 84
Issue: 4
Copyright Statement: © 2018 Wiley. This is the accepted version of an article which has been published in final form at https://dx.doi.org/10.1002/ana.25308
Sponsor/Funder: Multiple Sclerosis Society
Funder's Grant Number: 007/14
Keywords: Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
GENOME-WIDE ASSOCIATION
PARKINSONS-DISEASE
NEURODEGENERATIVE DISEASES
RICHARDSONS-SYNDROME
HUMAN BRAIN
DIAGNOSIS
RISK
CRITERIA
DEGENERATION
METAANALYSIS
Aged
Aged, 80 and over
Case-Control Studies
Cohort Studies
Female
Genetic Loci
Genetic Variation
Humans
Male
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Supranuclear Palsy, Progressive
Tripartite Motif Proteins
Ubiquitin-Protein Ligases
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
Neurology & Neurosurgery
1103 Clinical Sciences
1109 Neurosciences
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-07-31
Appears in Collections:Faculty of Medicine



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