Inkster, Becky, Nichols, Thomas E., Saemann, Philipp G., Auer, Dorothee P., Holsboer, Florian, Muglia, Pierandrea and Matthews, Paul M.. (2010) Pathway-based approaches to imaging genetics association studies: Wnt signaling, GSK3beta substrates and major depression. NeuroImage, Vol.53 (No.3). pp. 908-917. ISSN 1053-8119

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Abstract

Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3β) in mood disorders. We recently reported associations between GSK3β polymorphisms and brain structural changes in patients with recurrent major depressive disorder (MDD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3β biological functions are associated with similar regional grey matter (GM) volume changes in MDD patients. We tested specifically for associations with genetic variation in canonical Wnt signaling pathway genes and in genes that encode substrate proteins of GSK3β. We applied a general linear model with non-stationary cluster-based inference to examine associations between polymorphisms and regional voxel-based morphometry GM volume differences in recurrent MDD patients (n = 134) and in age-, gender-, and ethnicity-matched healthy controls (n = 144) to test for genotype-by-MDD interactions. We observed associations for polymorphisms in 8/13 canonical Wnt pathway genes and 5/10 GSK3β substrate genes, predominantly in the temporolateral and medial prefrontal cortices. Similar associations were not found for 100 unrelated polymorphisms tested. This work suggests that identifying SNPs related to genes that encode functionally-interacting proteins that modulate common anatomical regions offers a useful approach to increasing confidence in outcomes from imaging genetics association studies. This is of particular interest when replication datasets are not available. Our observations lend support to the hypothesis that polymorphisms in GSK3β play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions:	Faculty of Science > Statistics Faculty of Science > WMG (Formerly the Warwick Manufacturing Group)
Library of Congress Subject Headings (LCSH):	Cellular signal transduction, Genetic polymorphisms, Genetics, Depression, Mental
Journal or Publication Title:	NeuroImage
Publisher:	Elsevier
ISSN:	1053-8119
Date:	15 November 2010
Volume:	Vol.53
Number:	No.3
Number of Pages:	10
Page Range:	pp. 908-917
Identification Number:	10.1016/j.neuroimage.2010.02.065
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/38181

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