GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals
Autor: | John B.J. Kwok, Karen A. Mather, Leanne M. Williams, Peter R. Schofield, Nicola J. Armstrong, Carol Dobson-Stone, Evian Gordon, Perminder S. Sachdev, Mayuresh S. Korgaonkar, Wei Wen, Patsie Polly |
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Jazyk: | angličtina |
Rok vydání: | 2013 |
Předmět: |
Male
Anatomy and Physiology Transcription Genetic Epidemiology lcsh:Medicine Cohort Studies Glycogen Synthase Kinase 3 0302 clinical medicine Gene expression Promoter Regions Genetic lcsh:Science Octamer transcription factor Aged 80 and over Genetics 0303 health sciences Multidisciplinary biology Neurodegeneration Brain Organ Size Middle Aged medicine.anatomical_structure Genetic Epidemiology Medicine Female Alzheimer's disease Research Article Adult Genotype Tau protein tau Proteins Grey matter Polymorphism Single Nucleotide Neurological System Young Adult 03 medical and health sciences medicine Humans Biology GSK3B Alleles Genetic Association Studies Aged 030304 developmental biology Evolutionary Biology Glycogen Synthase Kinase 3 beta Polymorphism Genetic Population Biology Haplotype lcsh:R Computational Biology medicine.disease Neuroanatomy Genetic Polymorphism biology.protein lcsh:Q Population Genetics 030217 neurology & neurosurgery Neuroscience |
Zdroj: | PLoS ONE, Vol 8, Iss 8, p e71750 (2013) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037-0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082-0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders. |
Databáze: | OpenAIRE |
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