title: Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels.
abstract: BACKGROUND
  MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer's disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this.
  
  
  METHODS
  We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer's Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated.
  
  
  RESULTS
  H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03).
  
  
  CONCLUSIONS
  These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression.
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kachadoorian
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Quicksall
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
authors.forename: High Seng
authors.initials: HS
authors.lastname: Chai
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Younkin
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Malphrus
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Bisceglio
authors.affiliation: Medical Genome Facility, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Kolbert
authors.affiliation: Medical Genome Facility, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Departments of Biology, Neuroscience, Brigham Young University, Provo, UT 84602, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Kauwe
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Molecular Physiology and Biophysics, and the Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Gertrude H. Sergievsky Center, Department of Neurology, and Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: The John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Neurology, and Epidemiology, Boston University, Boston, MA, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neurology, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Birdsall 3, Jacksonville, FL 32224, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA ; Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Birdsall 3, Jacksonville, FL 32224, USA.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner