Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

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 atTRIM11. We found that TRIM11 is predominantly express...

Source: Annals of Neurology - October 16, 2018 Category: Neurology Authors: Edwin Jabbari, John Woodside, Manuela M. X. Tan, Maryam Shoai, Alan Pittman, Raffaele Ferrari, Kin Y. Mok, David Zhang, Regina H. Reynolds, Rohan de Silva, Max ‐Joseph Grimm, Gesine Respondek, Ulrich Müller, Safa Al‐Sarraj, Stephen M. G Tags: Research Article Source Type: research