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Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3beta) in mood disorders. We recently reported associations between GSK3beta 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 GSK3beta 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 GSK3beta. 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 GSK3beta 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 GSK3beta play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.

Original publication

DOI

10.1016/j.neuroimage.2010.02.065

Type

Journal article

Journal

Neuroimage

Publication Date

11/2010

Volume

53

Pages

908 - 917

Addresses

GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, London, UK.

Keywords

Humans, Genetic Predisposition to Disease, Glycogen Synthase Kinase 3, Magnetic Resonance Imaging, Brain Mapping, Depressive Disorder, Major, Signal Transduction, Genotype, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Wnt Proteins, Glycogen Synthase Kinase 3 beta