title: Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration.
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.
authors.affiliation: Clinical Neurosciences, Faculty of Human and Medical Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rizzu
authors.forename: Stephen
authors.initials: S
authors.lastname: Sikkink
authors.forename: Matthew
authors.initials: M
authors.lastname: Baker
authors.forename: Nicola
authors.initials: N
authors.lastname: Halliwell
authors.forename: Julie
authors.initials: J
authors.lastname: Snowden
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Dina
authors.initials: D
authors.lastname: Ruano
authors.forename: Nigel
authors.initials: N
authors.lastname: Cairns
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Martin
authors.initials: M
authors.lastname: Rossor
authors.forename: Ela
authors.initials: E
authors.lastname: Akay
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.forename: Elena
authors.initials: E
authors.lastname: Alonso
authors.forename: Pablo
authors.initials: P
authors.lastname: Martinez-Lage
authors.forename: Neil
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: David
authors.initials: D
authors.lastname: Neary
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
authors.forename: John
authors.initials: J
authors.lastname: Van Swieten
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C469867:UBAP1 protein, human