title: Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease.
abstract: BACKGROUND
  We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants.
  
  
  METHODS
  We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association.
  
  
  RESULTS
  We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6).
  
  
  CONCLUSIONS
  Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Barral
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lee
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kunkle
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Beecham
authors.affiliation: Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Cantwell
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine and Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine and Public Health, Boston, MA, USA; Department of Epidemiology, Boston University School of Medicine and Public Health, Boston, MA, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Department of Epidemiology, Human Genetics, and Environmental Sciences (EHGES), University of Texas School of Public Health at Houston, Houston, TX, USA; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA. Electronic address: rpm2@cumc.columbia.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods; D004293:Dominican Republic / Q000208:ethnology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009519:New York City; D020641:Polymorphism, Single Nucleotide; D011647:Puerto Rico / Q000208:ethnology
keywords: Caribbean Hispanic families; Joint linkage and association; Late-onset Alzheimer's disease; Linkage analysis