title: Family-based association between Alzheimer's disease and variants in UBQLN1.
abstract: BACKGROUND
  Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22.
  
  
  METHODS
  We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls.
  
  
  RESULTS
  In the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease.
  
  
  CONCLUSIONS
  Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown 02129, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.forename: Michele
authors.initials: M
authors.lastname: Parkinson
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Karunya
authors.initials: K
authors.lastname: Ramasamy
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.forename: Rashmi
authors.initials: R
authors.lastname: Menon
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sampson
authors.forename: Monica Y
authors.initials: MY
authors.lastname: Hsiao
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Elliott
authors.forename: Gonül
authors.initials: G
authors.lastname: Velicelebi
authors.forename: Thomas
authors.initials: T
authors.lastname: Moscarillo
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.forename: K David
authors.initials: KD
authors.lastname: Becker
authors.forename: Deborah
authors.initials: D
authors.lastname: Blacker
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: C079091:APBA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C107792:UBQLN1 protein, human