Elsevier

NeuroImage

Volume 53, Issue 3, 15 November 2010, Pages 908-917
NeuroImage

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

https://doi.org/10.1016/j.neuroimage.2010.02.065Get rights and content

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.

Introduction

Several imaging genetics studies have investigated associations of candidate gene variants with regional brain volume in patients with major depressive disorder (MDD) (Frodl et al., 2008a). Such findings hold promise for understanding the underlying mechanisms of depression, especially in light of recent meta-analytical evidence confirming MDD-specific volumetric changes in key brain regions, including the frontal lobe (especially the anterior cingulate, orbitofrontal and prefrontal cortices) (Drevets et al., 2008, Hajek et al., 2008, Koolschijn et al., 2009), the hippocampus, (Campbell & Macqueen, 2004, Koolschijn et al., 2009, Videbech & Ravnkilde, 2004), and the amygdala (in unmedicated patients) (Hamilton et al., 2008). However, confidence in imaging genetics findings has been limited by the lack of independent replications of associations. In part, this has been limited simply by the complexity and expense of acquiring sufficiently large imaging-based datasets. The heterogeneity of complex disease populations can also demand that the population sizes needed for reliable replication of true findings be so large as to challenge feasibility in the short term. This current study aims to provide an alternative strategy that addresses this issue by using two different biologically-informed approaches for strengthening the confidence in imaging genetics associations by testing polymorphisms in multiple functionally-related genes. We propose that, for true associations, functionally-related genes should also show anatomically similar associations with brain structural variations in the same dataset.

We recently reported associations of glycogen synthase kinase-3beta (GSK3β; OMIM 605004) polymorphisms with reduced grey matter (GM) volume in the right hippocampus and superior temporal gyrus (STG) in patients with recurrent MDD (Inkster et al., 2009). GSK3β encodes a highly pleiotropic serine/threonine protein kinase that regulates a diverse range of physiological functions in the brain (Jope & Johnson, 2004, Cohen & Frame, 2001). GSK3β plays a critical role via the canonical Wnt signaling pathway (as detailed in the Materials and methods section) in regulating neurodevelopment (Logan and Nusse, 2004), as well as synaptic maintenance and plasticity in the adult brain (Wexler et al., 2008, Peineau et al., 2008, Cerpa et al., 2008, Ahmad-Annuar et al., 2006). GSK3β modifies cellular responses post-translationally via phosphorylation of its multiple protein substrates, which consequently induce diverse effects in the brain related to cell proliferation, apoptosis, metabolism, transcription, protein synthesis, cell motility, axonal growth and microtubule dynamics (Jope & Johnson, 2004, Frame & Cohen, 2001).

In this study, we propose specifically that if genes encoding proteins in the canonical Wnt signaling pathway and those that act as GSK3β substrates contribute to the neurobiology of depression, then polymorphisms in these functionally-related genes should show disease-dependent and anatomically similar regional GM volume associations consistent with those we have previously reported for GSK3β (Inkster et al., 2009).

Section snippets

Subjects

Participants in this study are described in detail in our previously reported GSK3β association study (Inkster et al., 2009). In brief, the sample we studied is a subset of cases and controls belonging to a larger cohort of 1022 recurrent MDD patients and 1000 healthy controls (Tozzi et al., 2008). Participants were recruited and assessed at the Max Planck Institute of Psychiatry, Munich, Germany, except for 2 patients, who were recruited at satellite clinical sites (BKH Augsburg and Klinikum

Canonical Wnt signaling pathway genes

Genotype-by-MDD associations with regional GM volume differences were identified for SNPs on the Illumina chip in 8/13 of Wnt signaling pathway genes (Supplementary Table 1 shows all SNP associations). SNP associations with the minimum p-value include: rs10515969 (Tcf4), rs6980605 (Fzd3), rs385209 (Emx2), rs7224837 (Axin2), rs2074222 (Dvl2), rs13002663 (Zeb2), rs4956159 (Lef1) and rs934453 (Wnt7a) (which had PFWE(S,G) = 0.001, 0.001, 0.001, 0.014, 0.021, 0.024, 0.032 and 0.04, respectively). The

Discussion

We recently reported associations between GSK3β polymorphisms and brain regional GM volume changes in patients with major depression (Inkster et al., 2009). Sufficiently large datasets are not yet available to adequately test this finding by replication. We have therefore applied two novel, biological pathway-based approaches to evaluate functionally-related genetic associations with regional GM variation in order to assess the confidence in our originally reported GSK3β associations. Using the

Acknowledgments

We would like to acknowledge all patients and control subjects who have participated in this study. We would also like to thank the staff at the Max Planck Institute of Psychiatry, Munich, Germany, who contributed to this study, to Nicholas Simons for his manuscript comments, and to colleagues at GSK, in particular Anil Rao, Khanum Ridler, Federica Tozzi, Emilio Merlo-Pich and Sally Wetten for their contributions to the overall conduct of the study.

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