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
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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