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Published online before print May 28, 2008, doi:10.1212/01.wnl.0000304051.01650.23)
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NEUROLOGY 2008;71:28-34
© 2008 American Academy of Neurology

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

Authors' affiliations are listed at the end of the article.

Address correspondence and reprint requests to Dr. Jennifer E. Tobin, Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Room B2039, 4301 Jones Bridge Road, Bethesda, MD 20814 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.

Abbreviations: CBD = corticobasal degeneration; FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17; GEE = generalized estimating equations; HWE = Hardy-Weinberg equilibrium; LD = linkage disequilibrium; OR = odds ratio; PD = Parkinson disease; PSP = progressive supranuclear palsy; SNP = single-nucleotide polymorphism.

e-Pub ahead of print on May 28, 2008, at www.neurology.org.

Supported by the Bumpus Foundation, PHS grant R01 NS36711-05 (Genetic Linkage Study in PD), and NIA grant 5-T32-AG00277-05 (Neurobiology and Neuropsychology of Aging). DNA samples contributed by the Parkinson Institute-Istituti Clinici di Perfezionamento, Milan, Italy, were from the Human Genetic Bank of Patients Affected by PD and Parkinsonisms, supported by Italian Telethon grant GTF04007. The Harvard Brain Tissue Resource Center, which is supported in part by PHS grant R24 MH 068855, provided tissue used in this study. Boston University Alzheimer's Disease Center Brain Bank, is supported by the NIH, National Heart, Lung, and Blood Institute's Framingham Heart Study (NIH/NHLBI Contract N01-HC 25195), NIA 5R01-AG08122, NIA 5R01-AG 16495, and National Institute of Neurological Disorders and Stroke 2R01-NS17950, the Boston University Alzheimer's Disease Center NIAAA, P30 AG13846, and the Department of Veteran's Affairs. Dr. Stephen Kish at the Centre for Addiction and Mental Health at the University of Toronto provided additional brain tissue.

Editorial, page 11

Disclosure: The authors report no disclosures.

Received July 24, 2007. Accepted in final form November 5, 2007.






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