Rollinson, S and Rizzu, P and Sikkink, S and Baker, M and Halliwell, N and Snowden, J and Traynor, BJ and Ruano, D and Cairns, N and Rohrer, JD and Mead, S and Collinge, J and Rossor, M and Akay, E and Guerreiro, R and Rademakers, R and Morrison, KE and Pastor, P and Alonso, E and Martinez-Lage, P and Graff-Radford, N and Neary, D and Heutink, P and Mann, DMA and Van Swieten, J and Pickering-Brown, SM (2009) Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration. NEUROBIOL AGING , 30 (4) 656 - 665. 10.1016/j.neurobiolaging.2009.01.009.
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Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P = 0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P = 0.022), the USA (OR 1.4 95% CI 1.02-1.92, P = 0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P = 0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P = 0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43. (C) 2009 Elsevier Inc. All rights reserved.
|Title:||Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration|
|Keywords:||Frontotemporal lobar degeneration, UBAP1, Ubiquitin associated protein 1, TDP-43, Risk factor, NEURODEGENERATIVE DISEASE, HAPLOTYPE RECONSTRUCTION, DEMENTIA, MUTATIONS, PROGRANULIN, LOCUS, TAU, PATHOGENESIS, CONSENSUS, CRITERIA|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience|
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases
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