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Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder

Inkster, Beckya,b,c; Simmons, Andyd; Cole, James H.d,e; Schoof, Erwinj; Linding, Runej; Nichols, Tomg; Muglia, Pierandream; Holsboer, Florianl; Sämann, Philipp G.l; McGuffin, Peterd; Fu, Cynthia H.Y.d; Miskowiak, Kamillak; Matthews, Paul M.f; Zai, Gwynethn,o; Nicodemus, Kristinh,i

doi: 10.1097/YPG.0000000000000203

Objective 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.

Participants and methods 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.

Results 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.

Conclusion 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:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Received October 20, 2017

Received in revised form June 3, 2018

Accepted June 12, 2018

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