Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder
Inkster, Becky, Simmons, Andy, Cole, James, Schoof, Erwin, Linding, Rune, Nichols, Tom, Muglia, Pierandrea, Holsboer, Florian, Saemann, Philipp, McGuffin, Peter, Fu, C., Miskowiak, Kamilla, Matthews, Paul M., Zai, Gwyneth and Nicodemus, Kristin 2018. Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder. Psychiatric Genetics. 28 (5), pp. 77-84.
|Authors||Inkster, Becky, Simmons, Andy, Cole, James, Schoof, Erwin, Linding, Rune, Nichols, Tom, Muglia, Pierandrea, Holsboer, Florian, Saemann, Philipp, McGuffin, Peter, Fu, C., Miskowiak, Kamilla, Matthews, Paul M., Zai, Gwyneth and Nicodemus, Kristin|
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 a 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.
|Journal citation||28 (5), pp. 77-84|
|Publisher||Wolters Kluwer Health, Inc.|
|Accepted author manuscript|
File Access Level
Repository staff only
|Digital Object Identifier (DOI)||doi:10.1097/YPG.0000000000000203|
|Web address (URL)||https://doi.org/10.1097/YPG.0000000000000203|
|Online||03 Aug 2018|
|Publication process dates|
|Deposited||09 Aug 2018|
|Accepted||12 Jun 2018|
|Accepted||12 Jun 2018|
|National Institute for Health Research Biomedical Research Centre for Mental Health|
|National Institute for Health Research Biomedical Centre|
|Copyright information||© 2018 The authors|
|License||CC BY-NC 4.0|
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