Rollinson, Sara, Rizzu, Patrizia, Sikkink, Stephen, Baker, Matthew, Halliwell, Nicola, Snowden, Julie, Traynor, Bryan J., Ruano, Dina, Cairns, Nigel, Rohrer, Jonathan D., Mead, Simon, Collinge, John, Rossor, Martin, Akay, Ela, Guerreiro, Rita, Rademakers, Rosa, Morrison, Karen E., Pastor, Pau, Alonso, Elena, Martinez-Lage, Pablo, Graff-Radford, Neil, Neary, David, Heutink, Peter, Mann, David M.A., Van Swieten, John and Pickering-Brown, Stuart M. (2009) Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration. Neurobiology of Aging, 30 (4), 656-665. (doi:10.1016/j.neurobiolaging.2009.01.009).
Abstract
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.
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