Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report

Jee Su Suh; Laura M. Fiori; Mohammad Ali; Kate L. Harkness; Milita Ramonas; Luciano Minuzzi; Stefanie Hassel; Stephen C. Strother; Mojdeh Zamyadi; Stephen R. Arnott; Faranak Farzan; Jane A. Foster; Raymond W. Lam; Glenda M. MacQueen; Roumen Milev; Daniel J. Müller; Sagar V. Parikh; Susan Rotzinger; Roberto B. Sassi; Claudio N. Soares; Rudolf Uher; Sidney H. Kennedy; Gustavo Turecki; Benicio N. Frey

doi:10.1016/j.psyneuen.2021.105348

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report

Jee Su Suh, Laura M. Fiori, Mohammad Ali, Kate L. Harkness, Milita Ramonas, Luciano Minuzzi, Stefanie Hassel, Stephen C. Strother, Mojdeh Zamyadi, Stephen R. Arnott, Faranak Farzan, Jane A. Foster, Raymond W. Lam, Glenda M. MacQueen, Roumen Milev, Daniel J. Müller, Sagar V. Parikh, Susan Rotzinger, Roberto B. Sassi, Claudio N. SoaresRudolf Uher, Sidney H. Kennedy, Gustavo Turecki, Benicio N. Frey

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = −0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ² = 77.25, p < 0.0001) and NR3C1 (χ² = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

Original language	English (US)
Article number	105348
Journal	Psychoneuroendocrinology
Volume	132
DOIs	https://doi.org/10.1016/j.psyneuen.2021.105348
State	Published - Oct 2021
Externally published	Yes

Keywords

DNA methylation
Gene expression
Hypothalamus volume
Major depressive disorder
Neuroimaging

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology
Endocrine and Autonomic Systems
Psychiatry and Mental health
Biological Psychiatry

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10.1016/j.psyneuen.2021.105348

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Suh, J. S., Fiori, L. M., Ali, M., Harkness, K. L., Ramonas, M., Minuzzi, L., Hassel, S., Strother, S. C., Zamyadi, M., Arnott, S. R., Farzan, F., Foster, J. A., Lam, R. W., MacQueen, G. M., Milev, R., Müller, D. J., Parikh, S. V., Rotzinger, S., Sassi, R. B., ... Frey, B. N. (2021). Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report. Psychoneuroendocrinology, 132, Article 105348. https://doi.org/10.1016/j.psyneuen.2021.105348

Suh, JS, Fiori, LM, Ali, M, Harkness, KL, Ramonas, M, Minuzzi, L, Hassel, S, Strother, SC, Zamyadi, M, Arnott, SR, Farzan, F, Foster, JA, Lam, RW, MacQueen, GM, Milev, R, Müller, DJ, Parikh, SV, Rotzinger, S, Sassi, RB, Soares, CN, Uher, R, Kennedy, SH, Turecki, G & Frey, BN 2021, 'Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report', Psychoneuroendocrinology, vol. 132, 105348. https://doi.org/10.1016/j.psyneuen.2021.105348

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title = "Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report",

abstract = "Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = −0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.",

keywords = "DNA methylation, Gene expression, Hypothalamus volume, Major depressive disorder, Neuroimaging",

author = "Suh, {Jee Su} and Fiori, {Laura M.} and Mohammad Ali and Harkness, {Kate L.} and Milita Ramonas and Luciano Minuzzi and Stefanie Hassel and Strother, {Stephen C.} and Mojdeh Zamyadi and Arnott, {Stephen R.} and Faranak Farzan and Foster, {Jane A.} and Lam, {Raymond W.} and MacQueen, {Glenda M.} and Roumen Milev and M{\"u}ller, {Daniel J.} and Parikh, {Sagar V.} and Susan Rotzinger and Sassi, {Roberto B.} and Soares, {Claudio N.} and Rudolf Uher and Kennedy, {Sidney H.} and Gustavo Turecki and Frey, {Benicio N.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = oct,

doi = "10.1016/j.psyneuen.2021.105348",

language = "English (US)",

volume = "132",

journal = "Psychoneuroendocrinology",

issn = "0306-4530",

publisher = "Elsevier Limited",

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TY - JOUR

T1 - Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder

T2 - A CAN-BIND study report

AU - Suh, Jee Su

AU - Fiori, Laura M.

AU - Ali, Mohammad

AU - Harkness, Kate L.

AU - Ramonas, Milita

AU - Minuzzi, Luciano

AU - Hassel, Stefanie

AU - Strother, Stephen C.

AU - Zamyadi, Mojdeh

AU - Arnott, Stephen R.

AU - Farzan, Faranak

AU - Foster, Jane A.

AU - Lam, Raymond W.

AU - MacQueen, Glenda M.

AU - Milev, Roumen

AU - Müller, Daniel J.

AU - Parikh, Sagar V.

AU - Rotzinger, Susan

AU - Sassi, Roberto B.

AU - Soares, Claudio N.

AU - Uher, Rudolf

AU - Kennedy, Sidney H.

AU - Turecki, Gustavo

AU - Frey, Benicio N.

PY - 2021/10

Y1 - 2021/10

N2 - Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = −0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

AB - Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = −0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

KW - DNA methylation

KW - Gene expression

KW - Hypothalamus volume

KW - Major depressive disorder

KW - Neuroimaging

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U2 - 10.1016/j.psyneuen.2021.105348

DO - 10.1016/j.psyneuen.2021.105348

M3 - Article

C2 - 34229186

AN - SCOPUS:85109039818

SN - 0306-4530

VL - 132

JO - Psychoneuroendocrinology

JF - Psychoneuroendocrinology

M1 - 105348

ER -

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report

Abstract

Keywords

ASJC Scopus subject areas

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