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

Psychoneuroendocrinology. 2021 Oct:132:105348. doi: 10.1016/j.psyneuen.2021.105348. Epub 2021 Jun 29.

Authors

Jee Su Suh¹, Laura M Fiori², Mohammad Ali¹, Kate L Harkness³, Milita Ramonas⁴, Luciano Minuzzi⁵, Stefanie Hassel⁶, Stephen C Strother⁷, Mojdeh Zamyadi⁷, Stephen R Arnott⁷, Faranak Farzan⁸, Jane A Foster⁹, Raymond W Lam¹⁰, Glenda M MacQueen⁶, Roumen Milev¹¹, Daniel J Müller¹², Sagar V Parikh¹³, Susan Rotzinger¹⁴, Roberto B Sassi⁹, Claudio N Soares¹¹, Rudolf Uher¹⁵, Sidney H Kennedy¹⁶, Gustavo Turecki², Benicio N Frey¹⁷

Affiliations

¹ Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada.
² Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.
³ Department of Psychology, Queen's University, Kingston, ON, Canada.
⁴ Juravinski Hospital and Cancer Centre, Hamilton Health Sciences, Hamilton, ON, Canada.
⁵ Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
⁶ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁷ Rotman Research Institute, Baycrest, Toronto, ON, Canada.
⁸ eBrain Lab, School of Mechatronic Systems Engineering, Simon Fraser University, Surrey, BC, Canada.
⁹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
¹⁰ Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
¹¹ Departments of Psychiatry and Psychology, Queen's University, and Providence Care Hospital, Kingston, ON, Canada.
¹² Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Pharmacogenetics Research Clinic, Toronto, ON, Canada.
¹³ University of Michigan Depression Center, Ann Arbor, MI, United States.
¹⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
¹⁶ Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Depression and Suicide Studies, St. Michael's Hospital, Toronto, ON, Canada.
¹⁷ Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada. Electronic address: freybn@mcmaster.ca.

PMID: 34229186
DOI: 10.1016/j.psyneuen.2021.105348

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.

Trial registration: ClinicalTrials.gov NCT01655706.

Keywords: DNA methylation; Gene expression; Hypothalamus volume; Major depressive disorder; Neuroimaging.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers / metabolism
Canada
DNA Methylation* / genetics
Depressive Disorder, Major* / genetics
Depressive Disorder, Major* / pathology
Humans
Hypothalamo-Hypophyseal System / physiology
Hypothalamus* / pathology
Organ Size
Pituitary-Adrenal System / physiology
Receptors, Glucocorticoid / genetics
Receptors, Glucocorticoid / metabolism
Stress, Psychological* / genetics
Stress, Psychological* / physiopathology

Substances

Biomarkers
Receptors, Glucocorticoid

Associated data

ClinicalTrials.gov/NCT01655706

Grants and funding

MOP 125880/CIHR/Canada