Becky Inkster1,2,3, Andy Simmons4, James H Cole4,5, Erwin Schoof6, Rune Linding6, Tom Nichols7, Pierandrea Muglia8, Florian Holsboer9, Philipp G Sämann9, Peter McGuffin4, Cynthia H Y Fu4, Kamilla Miskowiak10, Paul M Matthews11, Gwyneth Zai12,13, Kristin Nicodemus14,15. 1. Department of Psychiatry. 2. Wolfson College, University of Cambridge. 3. Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge. 4. Institute of Psychiatry, Psychology and Neuroscience, Kings College London. 5. The Computational, Cognitive and Clinical Neuroimaging Laboratory, Department of Medicine. 6. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen. 7. Nuffield Department of Population Health, University of Oxford. 8. Medicine Development Centre, Genetics Division, Drug Discovery, GlaxoSmithKline, R&D, Verona, Italy. 9. Max Planck Institute Munich, Munich, Germany. 10. Department of Psychiatry, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark. 11. Department of Medicine, UK Dementia Research Institute, Imperial College London, London. 12. Molecular Brain Science Department, Neurogenetics Section, Centre for Addiction and Mental Health, Mood and Anxiety Division, Campbell Family Mental Health Research Institute. 13. Department of Psychiatry, University of Toronto, Toronto, Canada. 14. Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine. 15. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Abstract
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.
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.
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