Oral Presentation 9th GeneMappers Conference 2012

MAPT haplotype and promoter methylation and their implications for late-onset Parkinson’s disease. (#33)

Kirsten Coupland 1 2 , Carol Dobson-Stone 1 2 , George Mellick 3 , Woojin Kim 1 4 , Glenda Halliday 1 4 , John Kwok 1 4
  1. Neuroscience Research Australia, Randwick, NSW, Australia
  2. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  3. School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia
  4. Centre for Healthy Brain Aging, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects approximately 2% of the population over the age of 65. Several environmental factors, including smoking and pesticide exposure, have been shown to influence PD disease risk and have been hypothesised to act via an epigenetic mechanism [Warner and Schapira, 2003]. The microtubule-associated protein tau (MAPT) is a major susceptibility gene for late-onset PD, where the H1 haplotype is associated with increased risk of disease. We postulate that an additional aspect of the pathogenic mechanism associated with MAPT could be a genotype-specific methylation of the MAPT promoter. We determined the level of DNA methylation of 10 CpGs within a 65 bp region in the promoter in two cohorts. Lymphocyte DNA samples from the Queensland PD cohort (346 PD and 228 control) were analysed alongside 10 PD and 10 non-PD brain tissue DNA samples using bisulfite treatment and pyrosequencing. Logistic regression analysis revealed that MAPT methylation level was a significant predictor of disease status in brain tissue samples (p = 0.036). In lymphocyte samples MAPT methylation did not significantly predict disease status, but higher levels of methylation were significantly associated with a higher age of onset (β = 0.205 and p<0.0005). We also determined that MAPT haplotype was a significant predictor of methylation in lymphocyte DNAs (β = 0.329 and p<0.0005). Finally, we also observed a non-significant trend effect of smoking on MAPT methylation (β = -0.112, p = 0.096) in lymphocyte DNA from controls, but not in PD samples. This is the first study to demonstrate that differential methylation of MAPT is associated with two parameters of PD; disease state and age of onset. Our identification of a genotype-specific effect on methylation of the MAPT promoter has important implications in our understanding of the pathogenic mechanism of this neurodegenerative gene.

  1. Warner, T.T., Scharpira, A.H., 2003. Genetic and environmental factors in the cause of Parkinson’s disease. Ann Neurol. 53, 16-23.