Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype
| العنوان: | Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype |
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| المؤلفون: | Janice L. Holton, David Zhang, John Hardy, Max-Joseph Grimm, Rohan de Silva, Mina Ryten, Alan Pittman, Safa Al-Sarraj, Steve M. Gentleman, Regina H. Reynolds, Raffaele Ferrari, Manuela Tan, Edwin Jabbari, Andrew J. Lees, Maryam Shoai, Guenter U. Höglinger, Kin Y. Mok, Ulrich Müller, John Woodside, Gesine Respondek, Tamas Revesz, Thomas T. Warner, Huw R. Morris |
| المساهمون: | Multiple Sclerosis Society |
| المصدر: | Annals of Neurology Annals of neurology 84(4), 485-496 (2018). doi:10.1002/ana.25308 |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, Genome-wide association study, diagnosis [Supranuclear Palsy, Progressive], Cohort Studies, Tripartite Motif Proteins, PARKINSONS-DISEASE, CRITERIA, Research Articles, Genetics, genetics [Ubiquitin-Protein Ligases], RISK, Aged, 80 and over, genetics [Supranuclear Palsy, Progressive], DEGENERATION, Middle Aged, HUMAN BRAIN, genetics [Genetic Variation], Phenotype, Cohort, Female, RICHARDSONS-SYNDROME, Supranuclear Palsy, Progressive, Life Sciences & Biomedicine, Research Article, Ubiquitin-Protein Ligases, Clinical Neurology, Locus (genetics), Single-nucleotide polymorphism, genetics [Genetic Loci], Biology, DIAGNOSIS, Polymorphism, Single Nucleotide, genetics [Tripartite Motif Proteins], Progressive supranuclear palsy, medicine, SNP, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Gene, METAANALYSIS, Aged, Science & Technology, Neurology & Neurosurgery, Neurosciences, Genetic Variation, 1103 Clinical Sciences, medicine.disease, Minor allele frequency, Genetic Loci, Case-Control Studies, TRIM11 protein, human, Neurosciences & Neurology, NEURODEGENERATIVE DISEASES, 1109 Neurosciences |
| الوصف: | 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’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 (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/co-expression 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 – OR 5.5 (3.2-10.0), 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 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.InterpretationOur 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1531-8249 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd8b103583ef8ce492a66ed5a6ca0fdb https://pubmed.ncbi.nlm.nih.gov/30066433 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....fd8b103583ef8ce492a66ed5a6ca0fdb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15318249 |
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