GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.
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.
Neuroscience Research Australia, Randwick, New South Wales, Australia.
Carol
C
Dobson-Stone
Patsie
P
Polly
Mayuresh S
MS
Korgaonkar
Leanne M
LM
Williams
Evian
E
Gordon
Peter R
PR
Schofield
Karen
K
Mather
Nicola J
NJ
Armstrong
Wei
W
Wen
Perminder S
PS
Sachdev
John B J
JB
Kwok
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001921:Brain / Q000033:anatomy & histology* / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D055815:Young Adult; D016875:tau Proteins / Q000235:genetics*
C054369:MAPT protein, human; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3