Cover Image

Genetic Variant of Glucocorticoid Receptor Gene at rs41423247 and Its Association with Major Depressive Disorder: A Case-Control Study

Negar Firouzabadi, Hasti Nouraei, Ali Mandegary

Background: Extensive distribution of glucocorticoid receptors (GCRs) in different brain areas along with disruption of hypothalamic-pituitary-adrenal (HPA) axis in major depressive disorder (MDD) and the cross talk between GCRs and HPA proposes genetic variants of GC receptor genes as potential contributors in MDD. Among the GCR polymorphisms, rs41423247, rs6195 and rs6189/rs6190 are suggested to be involved in MDD.Materials and Methods: We investigated the association between rs41423247, rs6195 and rs6189/rs6190 and MDD in a case-control study. One hundred MDD patients along with 100 healthy individuals were enrolled in this study. genetic variants of rs41423247, rs6195 and rs6189/rs6190 were determined in extracted DNAs using PCR-RFLP.Result: The prevalence of heterozygote and mutant carriers of rs41423247 were significantly and by 1.9 fold greater in cases versus controls (P=0.033; OR; 95%CI=1.9; 1.1-3.3). Moreover, carriers of the mutant (G) allele were by 1.8 fold more prevalent in MDD group (P=0.013; OR;95%CI=1.8; 1.1-2.8).Conclusion: Specific carriers of rs41423247 might be more susceptible to developing MDD. This supports the hypothesis of the involvement of GCRs in pathophysiology of MDD. [GMJ.2018;7:e995]

Glucocorticoid receptor, Genetic variant, Single nucleotide polymorphism, Major depressive disorder

Belmaker R, Agam G. Major depressive disorder. N Engl j Med. 2008;2008(358):55-68.


Marcus M, Yasamy MT, van Ommeren M, Chisholm D, Saxena S. Depression: A global public health concern. WHO Department of Mental Health and Substance Abuse. 2012;1:6-8.

Blazer DG, Kaplan BH. Controversies in community-based psychiatric epidemiology: let the data speak for themselves. Archives of general psychiatry. 2000;57(3):227-8.

Kim Y-K, Na K-S, Shin K-H, Jung H-Y, Choi S-H, Kim J-B. Cytokine imbalance in the pathophysiology of major depressive disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2007;31(5):1044-53.


Lopez-Leon S, Janssens A, Ladd AG-Z, Del-Favero J, Claes S, Oostra B et al. Meta-analyses of genetic studies on major depressive disorder. Molecular psychiatry. 2008;13(8):772.


Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC et al. Stressful life events, genetic liability, and onset of an episode of major depression in women. Focus. 2010;8(3):459-70.

Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. American Journal of Psychiatry. 2003;160(9):1554-65.


Solomon MB, Furay AR, Jones K, Packard AE, Packard BA, Wulsin AC et al. Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females. Neuroscience. 2012;203:135-43.

PMid:22206943 PMCid:PMC4000316

Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain, behavior, and immunity. 2007;21(1):9-19.

PMid:17070667 PMCid:PMC1820632

Pariante CM. Glucocorticoid receptor function in vitro in patients with major depression. Stress. 2004;7(4):209-19.


Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23(5):477.

Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biological psychiatry. 2001;49(5):391-404.

Vreeburg SA, Hoogendijk WJ, van Pelt J, DeRijk RH, Verhagen JC, van Dyck R et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Archives of general psychiatry. 2009;66(6):617-26.


Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosomatic medicine. 2011;73(2):114-26.


Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC et al. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Frontiers in neuroendocrinology. 2003;24(3):151-80.


Herman JP, Ostrander MM, Mueller NK, Figueiredo H. Limbic system mechanisms of stress regulation: Hypothalamo-pituitary- adrenocortical axis. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2005;29(8):1201-13. doi:10.1016/j.pnpbp.2005.08.006.

Calfa G, Kademian S, Ceschin D, Vega G, Rabinovich G, Volosin M. Characterization and functional significance of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment. Psychoneuroendocrinology. 2003;28(5):687-701.

Modell S, Yassouridis A, Huber J, Holsboer F. Corticosteroid receptor function is decreased in depressed patients. Neuroendocrinology. 1997;65(3):216-22.


Pariante CM, Makoff A, Lovestone S, Feroli S, Heyden A, Miller AH et al. Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters. British journal of pharmacology. 2001;134(6):1335-43.

PMid:11704655 PMCid:PMC1573058

Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Molecular psychiatry. 2011;16(7):738.

PMid:21483429 PMCid:PMC3121947

Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M et al. Long‐term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. Journal of neuroendocrinology. 1995;7(11):841-5.


Won E, Kang J, Kim A, Choi S, Han K-M, Tae WS et al. Influence of BclI C/G (rs41423247) on hippocampal shape and white matter integrity of the parahippocampal cingulum in major depressive disorder. Psychoneuroendocrinology. 2016;72:147-55.


Castellini G, Lelli L, Tedde A, Piaceri I, Bagnoli S, Lucenteforte E et al. Analyses of the role of the glucocorticoid receptor gene polymorphism (rs41423247) as a potential moderator in the association between childhood overweight, psychopathology, and clinical outcomes in Eating Disorders patients: A 6 years follow up study. Psychiatry research. 2016;243:156-60.


Van Rossum EF, Koper JW, Van Den Beld AW, Uitterlinden AG, Arp P, Ester W et al. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clinical endocrinology. 2003;59(5):585-92.


Huizenga NA, Koper JW, de Lange P, Pols HA, Stolk RP, Burger H et al. A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo. The Journal of Clinical Endocrinology & Metabolism. 1998;83(1):144-51.

van Rossum EF, Koper JW, Huizenga NA, Uitterlinden AG, Janssen JA, Brinkmann AO et al. A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes. 2002;51(10):3128-34.


Association D-AP. Diagnostic and statistical manual of mental disorders. Arlington: American Psychiatric Publishing. 2013.

Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry. 1960;23(1):56.

Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic acids research. 1988;16(3):1215.

PMid:3344216 PMCid:PMC334765

Nouraei H, Firouzabadi N, Mandegary A, Zomorrodian K, Bahramali E, Shayesteh MRH et al. Glucocorticoid Receptor Genetic Variants and Response to Fluoxetine in Major Depressive Disorder. The Journal of neuropsychiatry and clinical neurosciences. 2017;30:45-50.


Demyttenaere K, Bruffaerts R, Posada-Villa J, Gasquet I, Kovess V, Lepine J et al. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. Jama. 2004;291(21):2581-90.


Brambilla F. Psychoneuroendocrinology: research on the pituitary adrenal-cortical system. Psychosomat Med. 2000;62:576-607.

Wüst S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. The Journal of Clinical Endocrinology & Metabolism. 2004;89(2):565-73.


Buttgereit F, Burmester G-R, Lipworth BJ. Optimised glucocorticoid therapy: the sharpening of an old spear. The Lancet. 2005;365(9461):801-3.

Arnett MG, Kolber BJ, Boyle MP, Muglia LJ. Behavioral insights from mouse models of forebrain-and amygdala-specific glucocorticoid receptor genetic disruption. Molecular and cellular endocrinology. 2011;336(1):2-5.

PMid:21094675 PMCid:PMC3172614

McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005;54(5):20-3.


Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocrine reviews. 1996;17(3):245-61.


van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biological psychiatry. 2006;59(8):681-8.


Gałecka E, Szemraj J, Bieńkiewicz M, Majsterek I, Przybyłowska-Sygut K, Gałecki P et al. Single nucleotide polymorphisms of NR3C1 gene and recurrent depressive disorder in population of Poland. Molecular biology reports. 2013;40(2):1693-9.

PMid:23073785 PMCid:PMC3538010

Krishnamurthy P, Romagni P, Torvik S, Gold P, Charney D, Detera-Wadleigh S et al. Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression. Hormone and metabolic research. 2008;40(03):194-8.


Brouwer JP, Appelhof BC, van Rossum EF, Koper JW, Fliers E, Huyser J et al. Prediction of treatment response by HPA-axis and glucocorticoid receptor polymorphisms in major depression. Psychoneuroendocrinology. 2006;31(10):1154-63.


Takahashi H, Yoshida K, Higuchi H, Kamata M, Inoue K, Suzuki T et al. Bcl1 Polymorphism of the Glucocorticoid Receptor Gene and Treatment Response to Milnacipran and Fluvoxamine in Japanese Patients with Depression. Neuropsychobiology. 2014;70(3):173-80.


Ventura-Juncá R, Symon A, López P, Fiedler JL, Rojas G, Heskia C et al. Relationship of cortisol levels and genetic polymorphisms to antidepressant response to placebo and fluoxetine in patients with major depressive disorder: a prospective study. BMC psychiatry. 2014;14(1):220.

PMid:25086452 PMCid:PMC4149200

Bet PM, Penninx BWJH, Bochdanovits Z, Uitterlinden AG, Beekman ATF, van Schoor NM et al. Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: New evidence for a gene–environment interaction. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2009;150B(5):660-9. doi:10.1002/ajmg.b.30886.

Bachmann AW, Sedgley TL, Jackson RV, Gibson JN, Young RM, Torpy DJ. Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology. 2005;30(3):297-306.


Panek M, Pietras T, Szemraj J, Kuna P. Association analysis of the glucocorticoid receptor gene (NR3C1) haplotypes (ER22/23EK, N363S, BclI) with mood and anxiety disorders in patients with asthma. Experimental and therapeutic medicine. 2014;8(2):662-70.

PMid:25009637 PMCid:PMC4079411


  • There are currently no refbacks.