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The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men

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Abstract

Genetic variations in the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) have been associated with maladaptive stress responses and major depressive disorder (MDD). In a case–control study design, we examined whether single nucleotide polymorphisms (SNPs) and haploid genotype (haplotype) associations of MR gene NR3C2, GR gene NR3C1 and genes of GR chaperone molecules FK506 binding protein 5 (FKBP5) and corticotrophin-releasing hormone receptor 1 (CRHR1) differed between healthy subjects (n = 634) and inpatients with major depressive disorder (n = 412). All analyses were conducted for women and men separately. After conservative correction of Type-I-error to obtain reliable p values, one SNP in the NR3C1 gene, namely rs6195, showed a significant association with the presence of a major depression (p = 0.048) in females. In contrast, NR3C2, FKBP5 and CRHR1 polymorphisms were not significantly associated with MDD. No haplotype effects could be identified. Our results support the notion of an association between variants of GR-related genes in women and the pathophysiology of depression: females suffering from MDD showed a more than three times higher frequency of the T/C polymorphism compared to controls, which thus seems to increase the vulnerability to depression in females.

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Author contributions

All authors have made substantive intellectual contributions to the submitted work in form of conception of the study, and/or acquisition of data, and/or analysis and interpretation of data, and/or drafting or revising the article. Nina Sarubin, Sven Hilbert, Anna-Maria Wimmer and Cornelius Schüle participated in acquisition of data and manuscript drafting; Caroline Nothdurfter, Rainer Rupprecht and Thomas C. Baghai participated in acquisition of data, manuscript editing and literature search; Cornelius Schüle was responsible for the concept of and conduction of the study; Felix Naumann, Sven Hilbert and Markus Bühner were responsible for the integrity of the data and the accuracy of the data analysis; Peter Zill was responsible for laboratory analysis; All authors approved the final version of the manuscript and take public responsibility for its content.

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    Authors and Affiliations

    1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336, Munich, Germany

      Nina Sarubin, Peter Zill, Anna-Maria Wimmer & Cornelius Schüle

    2. Department of Psychological Methodology and Assessment, Ludwig-Maximilians-University Munich, Munich, Germany

      Nina Sarubin, Sven Hilbert, Felix Naumann & Markus Bühner

    3. Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany

      Nina Sarubin, Caroline Nothdurfter, Rainer Rupprecht & Thomas C. Baghai

    4. Hochschule Fresenius, University of Applied Sciences, Munich, Germany

      Nina Sarubin

    5. Faculty of Psychology, Educational Science and Sport Science, University of Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany

      Sven Hilbert

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    Rainer Rupprecht has been on AstraZeneca advisory boards. Thomas C. Baghai accepted paid speaking engagements and acted as a consultant for Astra-Zeneca, Glaxo-Smith-Kline, Janssen-Cilag, Pfizer and Servier. Nina Sarubin, Caroline Nothdurfter, Sven Hilbert, Felix Naumann, Markus Bühner, Peter Zill, Anna-Maria Wimmer and Cornelius Schüle reported no direct or indirect financial or personal relationships, interests and affiliations relevant to the subject matter of the manuscript that have occurred over the last 3 years, or that are expected in the foreseeable future.

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    Nina Sarubin and Sven Hilbert contributed equally to this manuscript.

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    Sarubin, N., Hilbert, S., Naumann, F. et al. The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men. Eur Arch Psychiatry Clin Neurosci 267, 123–133 (2017). https://doi.org/10.1007/s00406-016-0722-5

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