Oral Presentation 9th GeneMappers Conference 2012

Brain Development and Neurodegeneration – MAPT and GSK3B Epistasis Affects Grey Matter and Intracranial Volume. (#47)

Carol Dobson-Stone 1 2 , Patsie Polly 2 , Karen Mather 3 , Nicola Armstrong 4 , Perminder Sachdev 5 , Henry Brodaty 6 , Evian Gordon 7 8 , Mayuresh Korgaonkar 7 , Lea Williams 7 , John BJ Kwok 1 2
  1. Neuroscience Research Australia, Randwick, NSW, Australia
  2. School of Medical Sciences, University of New South Wales, Sydney, Australia
  3. NPI - Euroa Centre, Prince of Wales Hospital, Sydney, Australia
  4. Cancer Program, Garvan Institute of Medical Research, Sydney, Australia
  5. School of Psychiatry, University of New South Wales, Sydney, Australia
  6. Dementia Collaborative Research Centre, University of New South Wales, Sydney, Australia
  7. Brain Dynamics Centre, University of Sydney, Sydney, Australia
  8. Brain Resource International Database, Sydney, Australia

The microtubule-associated protein Tau (MAPT) gene codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. Glycogen synthase kinase-3beta (GSK3B) gene codes for a serine/threonine kinase that phosphorylates various proteins, including Tau. Hyperphosphorylated Tau is deposited in various neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). We have previously shown that an epistatic interaction between MAPT and GSK3B increased risk of idiopathic neurodegenerative diseases.1  MAPT has also been associated with grey matter volume in specific brain areas of healthy adults.2  Of greater interest, a GWAS consortium identified the chromosome 17q21 inversion region, comprising MAPT and other genes, as a major locus that determines intracranial volume,3  suggesting a role for MAPT in brain development as well as neurodegeneration. We examined the effects of MAPT and a novel functional polymorphism in GSK3B (rs3755557) on total grey matter and intracranial volume in two community-living cohorts (Memory and Aging Study (MAS) and Brain Resource International Database (BRID)) comprising 590 neurologically healthy individuals. We show that rs3755557 alters transcriptional strength using a luciferase reporter assay and binding of at least two transcription factors, Oct-1 and Pbx-1a. We observed a significant sex-specific effect of GSK3B (rs3755557, beta = -0.13, p = 0.019, females) on age-independent intracranial volume in the pooled cohorts. Stratification analyses by MAPT H2 haplotype demonstrated a significant interaction between MAPT and GSK3B in predicting total grey matter (beta = -0.20, p = 0.017) and intracranial volume (beta = -0.19, p = 0.027) in the pooled cohorts. Our genetic and biochemical analyses have identified a novel interaction between MAPT and GSK3B in brain development, which can have important aetiological implications for multiple neurodegenerative disorders.

  1. Kwok JB et al. Glycogen synthase kinase-3beta and Tau Genes Interact in Alzheimer’s disease. Annals Neurology 55, 329-34 (2010).
  2. Canu E et al. H1 haplotype of the MAPT gene is associated with lower regional gray volume in healthy carriers. European Journal of Human Genetics 17, 287-294 (2009).
  3. Ikram MA et al. Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics 44, 539-544 (2012).