PT  - JOURNAL ARTICLE
AU  - E Jabbari
AU  - J Woodside
AU  - MMX Tan
AU  - M Shoai
AU  - A Pittman
AU  - R Ferrari
AU  - KY Mok
AU  - D Zhang
AU  - RH Reynolds
AU  - R de Silva
AU  - MJ Grimm
AU  - G Respondek
AU  - U Müller
AU  - S Al-Sarraj
AU  - SM Gentleman
AU  - AJ Lees
AU  - TT Warner
AU  - J Hardy
AU  - T Revesz
AU  - PROSPECT-UK consortium
AU  - GU Höglinger
AU  - JL Holton
AU  - M Ryten
AU  - HR Morris
AU  - PROSPECT-UK consortium:
AU  - E Jabbari
AU  - J Woodside
AU  - HR Morris
AU  - JB Rowe
AU  - PN Leigh
AU  - A Church
AU  - MTM Hu
AU  - C Kobylecki
AU  - N Pavese
AU  - G Carey
AU  - A Misbahuddin
AU  - S Molloy
AU  - O Bandmann
AU  - NK Archibald
AU  - BCP Ghosh
AU  - LA Massey
AU  - C Mann
AU  - DC Paviour
AU  - U Nath
AU  - E Capps
AU  - JC Sharma
AU  - P Critchley
AU  - K Amar
TI  - Variation at the <em>TRIM11</em> locus modifies Progressive Supranuclear Palsy phenotype
AID  - 10.1101/333195
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 333195
4099  - http://biorxiv.org/content/early/2018/06/05/333195.short
4100  - http://biorxiv.org/content/early/2018/06/05/333195.full
AB  - 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’s syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (n=497). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from the original PSP case-control GWAS. We assessed the expression/co-expression 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 – OR 5.55, p-value 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 LD with rs564309 replicated our findings. Gene based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed in neurons of 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.