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Multicenter Study
. 2008 Jul 1;71(1):28-34.
doi: 10.1212/01.wnl.0000304051.01650.23. Epub 2008 May 28.

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

J E Tobin  1 , J C Latourelle, M F Lew, C Klein, O Suchowersky, H A Shill, L I Golbe, M H Mark, J H Growdon, G F Wooten, B A Racette, J S Perlmutter, R Watts, M Guttman, K B Baker, S Goldwurm, G Pezzoli, C Singer, M H Saint-Hilaire, A E Hendricks, S Williamson, M W Nagle, J B Wilk, T Massood, J M Laramie, A L DeStefano, I Litvan, G Nicholson, A Corbett, S Isaacson, D J Burn, P F Chinnery, P P Pramstaller, S Sherman, J Al-hinti, E Drasby, M Nance, A T Moller, K Ostergaard, R Roxburgh, B Snow, J T Slevin, F Cambi, J F Gusella, R H Myers
Affiliations
Multicenter Study

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

J E Tobin et al. Neurology. .

Abstract

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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Figures

Figure 1
Figure 1. Linkage disequilibrium plot
Linkage disequilibrium of single-nucleotide polymorphisms in Parkinson disease cases was visualized as r2 values with darker squares representing higher r2 values. The pairwise r2 value is printed in each box of the grid. This plot was created using Haploview.
Figure 2
Figure 2. Relative gene expression
(A) The relative expression of MAPT, STH, and KIAA1267 represented as the mean ± SEM expression in Parkinson disease (PD) cases relative to controls. (B) The 4R:3R ratio of MAPT isoforms (mean ± SEM) in PD cases and controls. *p = 0.002, †p = 0.001, ‡p < 0.0001.
See this image and copyright information in PMC

Comment in

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