Pathway-based approaches to imaging genetics association studies: Wnt signaling, GSK3beta substrates and major depression

Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3 beta) in mood disorders. We recently reported associations between GSK3 beta polymorphisms and brain structural changes in patients with recurrent major depressive disorder (MOD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3 beta 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 GSK3 beta. 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 GSK3 beta 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 GSK3 beta play a role in MOD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates. (C) 2010 Elsevier Inc. All rights reserved.