Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Genetic Loci / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Supranuclear Palsy, Progressive / diagnosis*
  • Supranuclear Palsy, Progressive / genetics*
  • Tripartite Motif Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*


  • Tripartite Motif Proteins
  • TRIM11 protein, human
  • Ubiquitin-Protein Ligases