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Ann Neurol. 2018 Oct;84(4):485-496. doi: 10.1002/ana.25308. Epub 2018 Sep 15.

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.

Author information

1
Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, United Kingdom.
2
Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, United Kingdom.
3
Reta Lila Weston Institute, UCL Institute of Neurology, London, United Kingdom.
4
Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE); Department of Neurology, Technical University of Munich; Munich Cluster for Systems Neurology SyNergy, Munich, Germany.
5
Institute for Human Genetics, Justus Liebig University, Giessen, Germany.
6
MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, King's College London, London, United Kingdom.
7
Multiple Sclerosis and Parkinson's UK Brain Bank, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
8
Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, United Kingdom.

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. Ann Neurol 2018;84:485-496.

PMID:
30066433
PMCID:
PMC6221133
DOI:
10.1002/ana.25308
[Indexed for MEDLINE]
Free PMC Article

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