title: The Role of MAPT Haplotype H2 and Isoform 1N/4R in Parkinsonism of Older Adults.
abstract: OBJECTIVE
  Recently, we have shown that the Parkinson's disease (PD) susceptibility locus MAPT (microtubule associated protein tau) is associated with parkinsonism in older adults without a clinical diagnosis of PD. In this study, we investigated the relationship between parkinsonian signs and MAPT transcripts by assessing the effect of MAPT haplotypes on alternative splicing and expression levels of the most common isoforms in two prospective clinicopathologic studies of aging.
  
  
  METHODS
  using regression analysis, controlling for age, sex, study and neuropathology, we evaluated 976 subjects with clinical, genotyping and brain pathology data for haplotype analysis. For transcript analysis, we obtained MAPT gene and isoform-level expression from the dorsolateral prefrontal cortex for 505 of these subjects.
  
  
  RESULTS
  The MAPT H2 haplotype was associated with lower total MAPT expression (p = 1.2x10-14) and global parkinsonism at both study entry (p = 0.001) and proximate to death (p = 0.050). Specifically, haplotype H2 was primarily associated with bradykinesia in both assessments (p<0.001 and p = 0.008). MAPT total expression was associated with age and decreases linearly with advancing age (p<0.001). Analysing MAPT alternative splicing, the expression of 1N/4R isoform was inversely associated with global parkinsonism (p = 0.008) and bradykinesia (p = 0.008). Diminished 1N/4R isoform expression was also associated with H2 (p = 0.001).
  
  
  CONCLUSIONS
  Overall, our results suggest that age and H2 are associated with higher parkinsonism score and decreased total MAPT RNA expression. Additionally, we found that H2 and parkinsonism are associated with altered expression levels of specific isoforms. These findings may contribute to the understanding of the association between MAPT locus and parkinsonism in elderly subjects and in some extent to age-related neurodegenerative diseases.
authors.affiliation: Movement Disorders Clinic, Roberto Santos General Hospital, Salvador, BA, Brazil.|Health Sciences Center, Federal University of Reconcavo of Bahia, Santo Antonio de Jesus, BA, Brazil.|Post-Graduate Program in Health Sciences, Federal University of Bahia, Salvador, BA, Brazil.|Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Guilherme T
authors.identifier: http://orcid.org/0000-0003-3076-6384
authors.initials: GT
authors.lastname: Valenca
authors.affiliation: Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Gyan P
authors.initials: GP
authors.lastname: Srivastava
authors.affiliation: Post-Graduate Program in Health Sciences, Federal University of Bahia, Salvador, BA, Brazil.
authors.forename: Jamary
authors.initials: J
authors.lastname: Oliveira-Filho
authors.affiliation: Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.affiliation: Departments of Neurology, Molecular and Human Genetics, and Neuroscience, and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003933:Diagnosis; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000235:genetics; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D010641:Phenotype; D020033:Protein Isoforms; D019655:Quantitative Trait, Heritable; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D020033:Protein Isoforms; D016875:tau Proteins