RT Journal Article
SR Electronic
T1 Variation at the <em>TRIM11</em> locus modifies Progressive Supranuclear Palsy phenotype
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 333195
DO 10.1101/333195
A1 E Jabbari
A1 J Woodside
A1 MMX Tan
A1 M Shoai
A1 A Pittman
A1 R Ferrari
A1 KY Mok
A1 D Zhang
A1 RH Reynolds
A1 R de Silva
A1 MJ Grimm
A1 G Respondek
A1 U Müller
A1 S Al-Sarraj
A1 SM Gentleman
A1 AJ Lees
A1 TT Warner
A1 J Hardy
A1 T Revesz
A1 PROSPECT-UK consortium
A1 GU Höglinger
A1 JL Holton
A1 M Ryten
A1 HR Morris
A1 PROSPECT-UK consortium:
A1 E Jabbari
A1 J Woodside
A1 HR Morris
A1 JB Rowe
A1 PN Leigh
A1 A Church
A1 MTM Hu
A1 C Kobylecki
A1 N Pavese
A1 G Carey
A1 A Misbahuddin
A1 S Molloy
A1 O Bandmann
A1 NK Archibald
A1 BCP Ghosh
A1 LA Massey
A1 C Mann
A1 DC Paviour
A1 U Nath
A1 E Capps
A1 JC Sharma
A1 P Critchley
A1 K Amar
YR 2018
UL http://biorxiv.org/content/early/2018/06/05/333195.abstract
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.