Glycogen synthase kinase 3β (GSK3β) has been implicated in mood disorders. We previously reported associations between a GSK3β polymorphism and hippocampal volume in major depressive disorder (MDD). We then reported similar associations for a subset of GSK3β-regulated genes. We now investigate an algorithm-derived comprehensive list of genes encoding proteins that directly interact with GSK3β to identify a genotypic network influencing hippocampal volume in MDD.
We used discovery (N=141) and replication (N=77) recurrent MDD samples. Our gene list was generated from the NetworKIN database. Hippocampal measures were derived using an optimized Freesurfer protocol. We identified interacting single nucleotide polymorphisms using the machine learning algorithm Random Forest and verified interactions using likelihood ratio tests between nested linear regression models.
The discovery sample showed multiple two-single nucleotide polymorphism interactions with hippocampal volume. The replication sample showed a replicable interaction (likelihood ratio test: P=0.0088, replication sample; P=0.017, discovery sample; Stouffer’s combined P=0.0007) between genes associated previously with endoplasmic reticulum stress, calcium regulation and histone modifications.
Our results provide genetic evidence supporting associations between hippocampal volume and MDD, which may reflect underlying cellular stress responses. Our study provides evidence of biological mechanisms that should be further explored in the search for disease-modifying therapeutic targets for depression.
aDepartment of Psychiatry
bWolfson College, University of Cambridge
cCambridgeshire and Peterborough NHS Foundation Trust, Cambridge
dInstitute of Psychiatry, Psychology and Neuroscience, Kings College London
eThe Computational, Cognitive and Clinical Neuroimaging Laboratory, Department of Medicine
fDepartment of Medicine, UK Dementia Research Institute, Imperial College London, London
gNuffield Department of Population Health, University of Oxford
hCentre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine
iCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
jBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen
kDepartment of Psychiatry, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark
lMax Planck Institute Munich, Munich, Germany
mMedicine Development Centre, Genetics Division, Drug Discovery, GlaxoSmithKline, R&D, Verona, Italy
nMolecular Brain Science Department, Neurogenetics Section, Centre for Addiction and Mental Health, Mood and Anxiety Division, Campbell Family Mental Health Research Institute
oDepartment of Psychiatry, University of Toronto, Toronto, Canada
Correspondence to Becky Inkster, DPhil, Wolfson College, University of Cambridge, Cambridge CB2 8AH, UK Tel: +44 773 847 8045; fax: +44 122 333 5908; e-mail: firstname.lastname@example.org
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Received October 20, 2017
Received in revised form June 3, 2018
Accepted June 12, 2018