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Published online before print May 28, 2008, doi:10.1212/01.wnl.0000304051.01650.23)
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Received July 24, 2007
Accepted November 5, 2007

Haplotypes and gene expression implicate the MAPT region for Parkinson disease. The GenePD Study

J. E. Tobin PhD*, J. C. Latourelle MS, M. F. Lew MD, C. Klein MD, O. Suchowersky MD, H. A. Shill MD, L. I. Golbe MD, M. H. Mark MD, J. H. Growdon MD, G. F. Wooten MD, B. A. Racette MD, J. S. Perlmutter MD, R. Watts MD, M. Guttman MD, K. B. Baker PhD, S. Goldwurm MD, G. Pezzoli MD, C. Singer MD, M. H. Saint-Hilaire MD, A. E. Hendricks BA, S. Williamson BS, M. W. Nagle BA, J. B. Wilk DSc, T. Massood BS, J. M. Laramie PhD, A. L. DeStefano PhD, I. Litvan MD, G. Nicholson MD, A. Corbett MD, S. Isaacson MD, D. J. Burn MD, P. F. Chinnery MD, P. P. Pramstaller MD, S. Sherman MD, J. Al-hinti MD, E. Drasby MD, M. Nance MD, A. T. Moller MD, K. Ostergaard MD, PhD, R. Roxburgh PhD, B. Snow MD, J. T. Slevin MD, F. Cambi MD, J. F. Gusella PhD, and R. H. Myers PhD

From the Departments of Neurology (J.E.T., J.C.L., M.H.S.-H., A.E.H., S.W., M.W.N., J.B.W., T.M., J.M.L., A.L.D., R.H.M.), and Anatomy and Neurobiology (J.E.T.), Boston University School of Medicine; Department of Biostatistics (A.E.H., A.L.D.), Boston University School of Public Health; Department of Bioinformatics (J.M.L.), Boston University; Department of Neurology (M.F.L.), University of Southern California, Los Angeles; Department of Neurology (C.K.), Medical University of Lübeck, Germany; Departments of Clinical Neurosciences and Medical Genetics (O.S.), University of Calgary, Alberta, Canada; Barrow Neurological Institute (H.A.S.), Phoenix, AZ; Department of Neurology (L.I.G., M.H.M.), University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick; Department of Neurology (J.H.G.), Molecular Neurogenetics Unit (J.F.G.), Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology (G.F.W.), University of Virginia Health System, Charlottesville; Department of Neurology (B.A.R., J.S.P.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (R.W.), University of Alabama at Birmingham; Department of Medicine (M.G.), University of Toronto, Canada; Departments of Neurology and Neuroscience (K.B.B.), Cleveland Clinic Foundation; Parkinson Institute (S.G., G.P.), Istituti Clinici di Perfezionamento, Milan, Italy; Department of Neurology (C.S.), University of Miami, FL; Department of Neurology (I.L.), University of Louisville School of Medicine, KY; Neurology Department (G.N., A.C.), University of Sydney ANZAC Research Institute, Concord Hospital, Australia; Parkinson's Disease and Movement Disorder Center of Boca Raton (S.I.), FL; Regional Neurosciences Centre (D.J.B., P.F.C.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (P.P.P.), General Regional Hospital Bolzano, Italy; Department of Neurology (S.S.), University of Arizona, Tucson; Department of Neurology (J.A.), University of Arkansas for Medical Sciences; Port City Neurology (E.D.), Scarborough, ME; Park Nicollet Clinic (M.N.), St. Louis Park, MN; Department of Neurology (A.T.M., K.O.), Aarhus University Hospital, Denmark; Department of Neurology (R.R., B.S.), Auckland City Hospital, NewZealand; Department of Neurology (J.T.S., F.C.), University of Kentucky College of Medicine, Lexington.


* To whom correspondence should be addressed. E-mail: jetobinphd{at}gmail.com.

Background: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum.

Methods: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR.

Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT.

Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.




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