title: MAPT haplotype diversity in multiple system atrophy.
abstract: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as SNCA, COQ2 and LRRK2 have demonstrated that there is a genetic contribution to the disease. MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the MAPT H2 haplotype with MSA in 61 pathologically confirmed cases.
  
  
  
  In the present study, we assessed the full MAPT haplotype diversity in MSA patients using six MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls.
  
  
  
  We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%,
  
  
  
  22.7%, p = 0.024) and H1E (MSA:3.0%,
  
  
  
  9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%,
  
  
  
  1.3%, p = 0.030) and H1J (MSA:3.0%,
  
  
  
  0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001).
  
  
  
  Our findings provide further evidence that MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of MAPT and other genes in MSA.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Labbé
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Lorenzo-Betancor
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogaki
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Walton
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujioka
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Koga
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: van Gerpen
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Cheshire
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Low
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Sandroni
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Coon
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Singer
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA; Mayo Graduate School, Mayo Clinic, Jacksonville, FL, 32224, USA. Electronic address: ross.owen@mayo.edu.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D051844:alpha-Synuclein / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins
keywords: Association study; Genetics; MAPT; Multiple system atrophy