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Jabbari, Edwin; Woodside, John; Tan, Manuela M. X.; Shoai, Maryam; Pittman, Alan; Ferrari, Raffaele; Mok, Kin Y.; Zhang, David; Reynolds, Regina H.; Silva, Rohan de; Grimm, Max-Joseph; Respondek, Gesine; Müller, Ulrich; Al-Sarraj, Safa; Gentleman, Stephen M.; Lees, Andrew J.; Warner, Thomas T.; Hardy, John; Revesz, Tamas; Höglinger, Guenter U.; Holton, Janice L.; Ryten, Mina; Morris, Huw R. (2018): Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype. In: Annals of Neurology, Vol. 84, No. 4: pp. 485-496
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Objective/Methods: 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. 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 and Interpretation: 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=1.7x10(-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. 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