Abstract
Postpartum depression (PPD) is a common mood disorder that occurs after delivery with a prevalence of approximately 10%. Recent reports have related placental corticotropin-releasing hormone (pCRH) to postpartum depressive symptoms. The aim of this study was to determine whether pCRH, ACTH, and cortisol (measured 48 h after delivery) and glucocorticoid and mineralocorticoid receptor genotypes (NR3C1 and NR3C2) and their interaction are associated with PPD. A longitudinal 32-week prospective study of five hundred twenty-five Caucasian depression-free women that were recruited from obstetric units at two Spanish general hospitals immediately after delivery. Of the women included in the sample, forty-two (8%) developed PPD. A strong association between PPD and the interaction between the pCRH and NR3C2 rs2070951 genotype was observed. The mean level of pCRH in rs2070951GG carriers with PPD was 56% higher than the mean in the CG and CC genotype groups (P < 0.00005). Carriers of the rs2070951GG genotype with high levels of pCRH had a higher risk of developing PPD (OR = 1.020, 95% CI 1.007–1.034, P = 0.002). This association remained even after controlling for variables such as neuroticism, obstetric complications and the number of stressful life events during pregnancy. There is an important interaction between pCRH 48 h postpartum and the NR3C2 rs2070951GG genotype. This interaction moderately associates with the presence of PPD. These results may open a new line of research and, if confirmed in other settings, will help to identify better risk predictors and the treatment for PPD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arai K, Nakagomi Y, Iketani M, Shimura Y, Amemiya S, Ohyama K, Shibasaki T (2003) Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism. Hum Genet 112:91–97. https://doi.org/10.1007/s00439-002-0855-7
Baca-Garcia E, Parra CP, Perez-Rodriguez MM, Sastre CD, Torres RR, Saiz-Ruiz J, de Leon J (2007) Psychosocial stressors may be strongly associated with suicide attempts. Stress Health 23:191–198. https://doi.org/10.1002/smi.1137
Bauchet M, McEvoy B, Pearson LN, Quillen EE, Sarkisian T, Hovhannesyan K, Deka R, Bradley DG, Shriver MD (2007) Measuring European population stratification with microarray genotype data. Am J Hum Genet 80:948–956. https://doi.org/10.1086/513477
Chrousos GP, Torpy DJ, Gold PW (1998) Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 129:229–240
Costas J, Gratacos M, Escaramis G et al (2010) Association study of 44 candidate genes with depressive and anxiety symptoms in post-partum women. J PsychiatrRes 44:717–724
de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MHJ, Hasselmann H, Kliegel D, Joëls M (2016) Stress and depression: a crucial role of the mineralocorticoid receptor. J Neuroendocrinol 28. https://doi.org/10.1111/jne.12379
Derijk RH, van Leeuwen N, Klok MD, Zitman FG (2008) Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health. Eur J Pharmacol 585:492–501. https://doi.org/10.1016/j.ejphar.2008.03.012
Dudbridge F, Gusnanto A (2008) Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 32:227–234. https://doi.org/10.1002/gepi.20297
Engineer N, Darwin L, Nishigandh D, Ngianga-Bakwin K, Smith SC, Grammatopoulos DK (2013) Association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants and risk for depression during pregnancy and post-partum. J Psychiatr Res 47:1166–1173. https://doi.org/10.1016/j.jpsychires.2013.05.003
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science (New York, NY) 296:2225–2229. https://doi.org/10.1126/science.1069424
Garcia-Esteve L, Ascaso C, Ojuel J, Navarro P (2003) Validation of the Edinburgh Postnatal Depression Scale (EPDS) in Spanish mothers. J Affect Disord 75:71–76
Glynn LM, Sandman CA (2014) Evaluation of the association between placental corticotrophin-releasing hormone and postpartum depressive symptoms. Psychosom Med 76:355–362. https://doi.org/10.1097/PSY.0000000000000066
Iliadis SI, Sylvén S, Hellgren C, Olivier JD, Schijven D, Comasco E, Chrousos GP, Sundström Poromaa I, Skalkidou A (2016) Mid-pregnancy corticotropin-releasing hormone levels in association with postpartum depressive symptoms. Depress Anxiety 33(11):1023–1030. https://doi.org/10.1002/da.22529
Kalantaridou SN, Zoumakis E, Makrigiannakis A, Lavasidis LG, Vrekoussis T, Chrousos GP (2010) Corticotropin-releasing hormone, stress and human reproduction: an update. J Reprod Immunol 85:33–39. https://doi.org/10.1016/j.jri.2010.02.005
Kalueff AV, Stewart AM, Nguyen M, Song C, Gottesman II (2015) Targeting drug sensitivity predictors: new potential strategies to improve pharmacotherapy of human brain disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 63:76–82. https://doi.org/10.1016/j.pnpbp.2015.05.004
Klok MD, Giltay EJ, Van der Does AJW et al (2011) A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. Transl Psychiatry 1:e62. https://doi.org/10.1038/tp.2011.59
Magiakou MA, Mastorakos G, Rabin D et al (1996) Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 81:1912–1917. https://doi.org/10.1210/jc.81.5.1912
Meakin CJ, Martin EM, Santos HP et al (2018) Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm. Horm Behav 101:29–35. https://doi.org/10.1016/j.yhbeh.2018.02.007
Meltzer-Brody S, Stuebe A, Dole N, Savitz D, Rubinow D, Thorp J (2011) Elevated corticotropin releasing hormone (CRH) during pregnancy and risk of postpartum depression (PPD). J Clin Endocrinol Metab 96:E40–E47. https://doi.org/10.1210/jc.2010-0978
Menke A (2019) Is the HPA axis as target for depression outdated, or is there a new hope? Front Psychiatry 10:1–8. https://doi.org/10.3389/fpsyt.2019.00101
Naughton M, Dinan TG, Scott LV (2014) Corticotropin-releasing hormone and the hypothalamic-pituitary-adrenal axis in psychiatric disease. Handb Clin Neurol 124:69–91. https://doi.org/10.1016/B978-0-444-59602-4.00005-8
O’Hara MW (2009) Postpartum depression: what we know. J Clin Psychol 65:1258–1269. https://doi.org/10.1002/jclp.20644
Ortet G, Ibáñez M, Moro M, Silva F (2008) Cuestionario revisado de personalidad de Eysenck: versiones completa (EPQ-R) y abreviada (EPQ-RS). TEA Ediciones, Madrid
Paykel ES (1983) Methodological aspects of life events research. J Psychosom Res 27:341–352. https://doi.org/10.1016/0022-3999(83)90065-X
Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. https://doi.org/10.1086/519795
Refojo D, Holsboer F (2009) CRH signaling: molecular specificity for drug targeting in the CNS. Ann N Y Acad Sci 1179:106–119. https://doi.org/10.1111/j.1749-6632.2009.04983.x
Rich-Edwards JW, Mohllajee AP, Kleinman K, Hacker MR, Majzoub J, Wright RJ, Gillman MW (2008) Elevated midpregnancy corticotropin-releasing hormone is associated with prenatal, but not postpartum, maternal depression. J Clin Endocrinol Metab 93:1946–1951. https://doi.org/10.1210/jc.2007-2535
Roca M, Martin-Santos R, Saiz J, Obiols J, Serrano MJ, Torrens M, Subirà S, Gili M, Navinés R, Ibañez A, Nadal M, Barrantes N, Cañellas F (2007) Diagnostic Interview for Genetic Studies (DIGS): inter-rater and test-retest reliability and validity in a Spanish population. Eur Psychiatry 22:44–48. https://doi.org/10.1016/j.eurpsy.2006.10.004
Sanjuan J, Martin-Santos R, Garcia-Esteve L, Carot JM, Guillamat R, Gutierrez-Zotes A, Gornemann I, Canellas F, Baca-Garcia E, Jover M, Navines R, Valles V, Vilella E, de Diego Y, Castro JA, Ivorra JL, Gelabert E, Guitart M, Labad A, Mayoral F, Roca M, Gratacos M, Costas J, van Os J, de Frutos R (2008) Mood changes after delivery: role of the serotonin transporter gene. Br J Psychiatry J Ment Sci 193:383–388. https://doi.org/10.1192/bjp.bp.107.045427
Serati M, Redaelli M, Buoli M, Altamura AC (2016) Perinatal major depression biomarkers: a systematic review. J Affect Disord 193:391–404. https://doi.org/10.1016/j.jad.2016.01.027
Stergiakouli E, Sterne JAC, Smith GD (2014) Failure to replicate the association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants with risk of depression during pregnancy and post-partum reported by. J Psychiatr Res 56:168–170. https://doi.org/10.1016/j.jpsychires.2014.04.016
Stetler C, Miller GE (2011) Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med 73:114–126. https://doi.org/10.1097/PSY.0b013e31820ad12b
Stonawski V, Frey S, Golub Y, Rohleder N, Kriebel J, Goecke TW, Fasching PA, Beckmann MW, Kornhuber J, Kratz O, Moll GH, Heinrich H, Eichler A (2018) Associations of prenatal depressive symptoms with DNA methylation of HPA axis-related genes and diurnal cortisol profiles in primary school-aged children. Dev Psychopathol 31:1–13. https://doi.org/10.1017/S0954579418000056
Sullivan PF, de Geus EJC, Willemsen G, James MR, Smit JH, Zandbelt T, Arolt V, Baune BT, Blackwood D, Cichon S, Coventry WL, Domschke K, Farmer A, Fava M, Gordon SD, He Q, Heath AC, Heutink P, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hu Y, Kohli M, Lin D, Lucae S, MacIntyre DJ, Maier W, McGhee KA, McGuffin P, Montgomery GW, Muir WJ, Nolen WA, Nöthen MM, Perlis RH, Pirlo K, Posthuma D, Rietschel M, Rizzu P, Schosser A, Smit AB, Smoller JW, Tzeng JY, van Dyck R, Verhage M, Zitman FG, Martin NG, Wray NR, Boomsma DI, Penninx BWJH (2009) Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry 14:359–375. https://doi.org/10.1038/mp.2008.125
Tan E-C, Chua T-E, Lee TMY, Tan HS, Ting JLY, Chen HY (2015) Case-control study of glucocorticoid receptor and corticotrophin-releasing hormone receptor gene variants and risk of perinatal depression. BMC Pregnancy Childbirth 15:283. https://doi.org/10.1186/s12884-015-0720-z
ter Heegde F, De Rijk RH, Vinkers CH (2015) The brain mineralocorticoid receptor and stress resilience. Psychoneuroendocrinology 52:92–110. https://doi.org/10.1016/j.psyneuen.2014.10.022
Thomson M (2013) The physiological roles of placental corticotropin releasing hormone in pregnancy and childbirth. J Physiol Biochem 69:559–573. https://doi.org/10.1007/s13105-012-0227-2
van Leeuwen N, Kumsta R, Entringer S, de Kloet ER, Zitman FG, DeRijk RH, Wüst S (2010) Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone. Psychoneuroendocrinology 35:339–349. https://doi.org/10.1016/j.psyneuen.2009.07.006
van Leeuwen N, Bellingrath S, de Kloet ER, Zitman FG, DeRijk RH, Kudielka BM, Wüst S (2011) Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response. Psychoneuroendocrinology 36:699–709. https://doi.org/10.1016/j.psyneuen.2010.10.003
Yim IS, Glynn LM, Dunkel-Schetter C et al (2009) Risk of postpartum depressive symptoms with elevated corticotropin-releasing hormone in human pregnancy. Arch Gen Psychiatry 66:162–169. https://doi.org/10.1001/archgenpsychiatry.2008.533
Role of the funding sources
This work was supported by the Instituto de Salud Carlos III (Spanish Ministry of Health) grant numbers PI04/2007.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Disclaimer
The Instituto de Salud Carlos III had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gutiérrez-Zotes, A., Díaz-Peña, R., Costas, J. et al. Interaction between the functional SNP rs2070951 in NR3C2 gene and high levels of plasma corticotropin-releasing hormone associates to postpartum depression. Arch Womens Ment Health 23, 413–420 (2020). https://doi.org/10.1007/s00737-019-00989-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00737-019-00989-x