Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.

Edwin Jabbari,Mina Ryten,David Zhang,Thomas T Warner,Maryam Shoai,Janice L Holton,Andrew J Lees,Rohan De Silva,Safa Al‐Sarraj,John Woodside,Alan Pittman,Huw R Morris,Gesine Respondek,Raffaele Ferrari,John Hardy,Stephen M Gentleman,Kin Y Mok,Günter U Höglinger,Ulrich Müller,Max‐Joseph Grimm,Tamás Révész ,Regina H Reynolds ,Manuela Tan

doi:10.1002/ana.25308

Abstract

ObjectiveThe 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.MethodsTwo 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.ResultsOur 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.InterpretationOur 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

Highlights

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative condition and the most common cause of atypical parkinsonism, with an estimated prevalence of 5-7 per 100,000 [1]
We show that variation at the chromosome 1q42.13 locus determines clinical phenotype in PSP with a very strong effect size
The validity of our genome wide association study (GWAS) results is increased by the fact that similar sized association signals and minor allele frequencies were observed in two independent cohorts with a genome-wide significant association achieved when the two cohorts were combined

Summary

Introduction

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative condition and the most common cause of atypical parkinsonism, with an estimated prevalence of 5-7 per 100,000 [1]. The pathology of PSP is centred on the structural microtubule associated protein tau, encoded by the MAPT gene located on chromosome 17. The pathological hallmarks of PSP include a high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brainstem along with tau-positive tufted astrocytes [2]. Richardson’s syndrome (RS) is the most common clinical phenotype related to PSP pathology – first described by Steele, Richardson and Olszewski as a levodopaunresponsive akinetic-rigid syndrome with falls, a vertical supranuclear gaze palsy and dementia [3]. A clinical diagnosis of RS has been shown to be highly predictive of underlying PSP pathology [5], and the diagnosis of this form of PSP was operationalised in the NINDSSPSP criteria [6]

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