Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder
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Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder. / Inkster, Becky; Simmons, Andy; Cole, James H.; Schoof, Erwin; Linding, Rune; Nichols, Tom; Muglia, Pierandrea; Holsboer, Florian; Sämann, Philipp G.; McGuffin, Peter; Fu, Cynthia H.Y.; Miskowiak, Kamilla; Matthews, Paul M.; Zai, Gwyneth; Nicodemus, Kristin.
In: Psychiatric Genetics, Vol. 28, No. 5, 2018, p. 77-84.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder
AU - Inkster, Becky
AU - Simmons, Andy
AU - Cole, James H.
AU - Schoof, Erwin
AU - Linding, Rune
AU - Nichols, Tom
AU - Muglia, Pierandrea
AU - Holsboer, Florian
AU - Sämann, Philipp G.
AU - McGuffin, Peter
AU - Fu, Cynthia H.Y.
AU - Miskowiak, Kamilla
AU - Matthews, Paul M.
AU - Zai, Gwyneth
AU - Nicodemus, Kristin
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - endoplasmic reticulum stress
KW - glycogen synthase kinase 3β
KW - hippocampus
KW - histone deacetylase modifications
KW - major depressive disorder
KW - network
U2 - 10.1097/YPG.0000000000000203
DO - 10.1097/YPG.0000000000000203
M3 - Journal article
C2 - 30080747
AN - SCOPUS:85054004914
VL - 28
SP - 77
EP - 84
JO - Psychiatric Genetics
JF - Psychiatric Genetics
SN - 0955-8829
IS - 5
ER -
ID: 211856582