TY - JOUR
T1 - Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration
AU - Rollinson, Sara
AU - Rizzu, Patrizia
AU - Sikkink, Stephen
AU - Baker, Matthew
AU - Halliwell, Nicola
AU - Snowden, Julie
AU - Traynor, Bryan J.
AU - Ruano, Dina
AU - Cairns, Nigel
AU - Rohrer, Jonathan D.
AU - Mead, Simon
AU - Collinge, John
AU - Rossor, Martin
AU - Akay, Ela
AU - Guerreiro, Rita
AU - Rademakers, Rosa
AU - Morrison, Karen E.
AU - Pastor, Pau
AU - Alonso, Elena
AU - Martinez-Lage, Pablo
AU - Graff-Radford, Neil
AU - Neary, David
AU - Heutink, Peter
AU - Mann, David M.A.
AU - Van Swieten, John
AU - Pickering-Brown, Stuart M.
PY - 2009/4/1
Y1 - 2009/4/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.neurobiolaging.2009.01.009
DO - 10.1016/j.neurobiolaging.2009.01.009
M3 - Article
SN - 0197-4580
VL - 30
SP - 656
EP - 665
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 4
ER -