Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration.
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.
Rollinson
Sara
S
Clinical Neurosciences, Faculty of Human and Medical Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Rizzu
Patrizia
P
Sikkink
Stephen
S
Baker
Matthew
M
Halliwell
Nicola
N
Snowden
Julie
J
Traynor
Bryan J
BJ
Ruano
Dina
D
Cairns
Nigel
N
Rohrer
Jonathan D
JD
Mead
Simon
S
Collinge
John
J
Rossor
Martin
M
Akay
Ela
E
Guerreiro
Rita
R
Rademakers
Rosa
R
Morrison
Karen E
KE
Pastor
Pau
P
Alonso
Elena
E
Martinez-Lage
Pablo
P
Graff-Radford
Neil
N
Neary
David
D
Heutink
Peter
P
Mann
David M A
DM
Van Swieten
John
J
Pickering-Brown
Stuart M
SM
D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D003704:Dementia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011110:Polymorphism, Genetic / Q000235:genetics*; D013030:Spain; D055815:Young Adult
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C469867:UBAP1 protein, human