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      Case-control study of glucocorticoid receptor and corticotrophin-releasing hormone receptor gene variants and risk of perinatal depression

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          Abstract

          Background

          Depression during pregnancy or after childbirth is the most frequent perinatal illness affecting women of reproductive age. It could result in unfavourable outcomes for both women and their newborns. The incidence of perinatal depression is higher for those with family history of depression and other mental illness, suggesting the contribution of genetic factors. There is postulation that disruption or fluctuation of reproductive hormones could play a part in women who are sensitive to such changes.

          Methods

          This is a case-control study comparing the frequencies of candidate gene variants in patients with perinatal depression with controls. Patients of Chinese descent ( N = 725) were recruited from the outpatient clinics of the hospital between 2010 and 2013. Controls were patients who came for postnatal consultations at the obstetrics clinics and scored ≤ 7 on the Edinburgh Postnatal Depression Scale (EPDS) at the postnatal screening programme of the hospital. Cases with confirmed diagnosis of clinical (major) depression related to pregnancy/postpartum were recruited from the hospital’s outpatient clinic. Genomic DNA was extracted from saliva samples and genotyped for the polymorphisms of interest. Differences between groups were assessed by chi-square analysis.

          Results

          CRHR1 rs242939 and rs1876828 were not polymorphic in the study population. There was no statistically significant association of perinatal depression for CRHR1 rs242941 and GR rs41423247 ( BclI). When all subjects were grouped based on family history of mental illness, there was a statistically significant association of CRHR1 rs242941 with family history regardless of depression status ( P = 0.043). There was also a statistically significant difference for GR rs41423247 and regularity of menstrual periods ( P < 0.000). Although not statistically significant, women with perinatal depression showed a trend towards higher frequency of self-reported menstrual irregularity.

          Conclusions

          No evidence was found for the association of any of the genetic markers with perinatal depression in this study cohort. Instead, the possible genetic links were found in women with positive family history of mental illness and menstrual irregularity, suggesting these could be identifying risk markers for women.

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          Most cited references44

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          Cohort study of depressed mood during pregnancy and after childbirth.

          To follow mothers' mood through pregnancy and after childbirth and compare reported symptoms of depression at each stage. Longitudinal cohort study. Avon. Pregnant women resident within Avon with an expected date of delivery between 1 April 1991 and 31 December 1992. Symptom scores from the Edinburgh postnatal depression scale at 18 and 32 weeks of pregnancy and 8 weeks and 8 months postpartum. Proportion of women above a threshold indicating probable depressive disorder. Depression scores were higher at 32 weeks of pregnancy than 8 weeks postpartum (difference in means 0.88, 95% confidence interval 0.79 to 0.97). There was no difference in the distribution of total scores or scores for individual items at the four time points. 1222 (13.5%) women scored above threshold for probable depression at 32 weeks of pregnancy, 821 (9.1%) at 8 weeks postpartum, and 147 (1.6%) throughout. More mothers moved above the threshold for depression between 18 weeks and 32 weeks of pregnancy than between 32 weeks of pregnancy and 8 weeks postpartum. Symptoms of depression are not more common or severe after childbirth than during pregnancy. Research and clinical efforts need to be moved towards understanding, recognising, and treating antenatal depression.
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            Overview of the genetics of major depressive disorder.

            Major depressive disorder (MDD) is a common psychiatric illness with high levels of morbidity and mortality. Despite intensive research during the past several decades, the neurobiological basis and pathophysiology of depressive disorders remain unknown. Genetic factors play important roles in the development of MDD, as indicated by family, twin, and adoption studies, and may reveal important information about disease mechanisms. This article describes recent developments in the field of psychiatric genetics, with a focus on MDD. Early twin studies, linkage studies, and association studies are discussed. Recent findings from genome-wide association studies are reviewed and future directions discussed. Despite all efforts, thus far, no single genetic variation has been identified to increase the risk of depression substantially. Genetic variants are expected to have only small effects on overall disease risk, and multiple genetic factors in conjunction with environmental factors are likely necessary for the development of MDD. Future large-scale studies are needed to dissect this complex phenotype and to identify pathways involved in the etiology of MDD.
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              Clinical features associated with glucocorticoid receptor polymorphisms. An overview.

              The glucocorticoid receptor (GR) is crucial for the effects of glucocorticoids (GCs). Several polymorphisms of the GR are associated with altered sensitivity to GCs. For the ER22/23EK polymorphism, a relative GC resistance has been demonstrated. In vivo, this was suggested by a smaller response to a dexamethasone suppression test (DST), whereas in vitro experiments showed a diminished transactivational activity. The associated features of ER22/23EK carriers consist of favorable metabolic and body compositional conditions. In elderly subjects this polymorphism was associated with longevity and decreased risk of dementia. Interestingly, recent studies also showed an increased risk of major depression. In contrast, the N363S polymorphism was reported to be associated with an enhanced sensitivity to GCs, as was demonstrated by a DST. This polymorphism has also been associated with increased body mass index (BMI) and LDL-cholesterol levels, as well as increased risk of cardiovascular disease. However, additional studies yielded conflicting results, showing no associations with being overweight. The BclI polymorphism is also associated with increased GC sensitivity. In addition, associations with increased abdominal fat mass, Crohn's disease and, remarkably, major depression have been reported. Another GR polymorphism, located in exon 9beta, is associated with increased expression and stabilization of the dominant negative splice variant GR-beta. Carriers of this polymorphism displayed a relative GC resistance in vitro as evidenced by diminished transrepressional activity, which is important for the immune system and inflammation. Associations have been found with increased inflammatory parameters, cardiovascular disease, and rheumatoid arthritis. In this article, studies concerning these clinically relevant GR variants are discussed.
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                Author and article information

                Contributors
                +65 63943792 , tanec@bigfoot.com
                chua.tze.ern@singhealth.com.sg
                theresa.lee.m.y@singhealth.com.sg
                suzannetan85@gmail.com
                joe.ting@kcl.ac.uk
                helen.chen.y@singhealth.com.sg
                Journal
                BMC Pregnancy Childbirth
                BMC Pregnancy Childbirth
                BMC Pregnancy and Childbirth
                BioMed Central (London )
                1471-2393
                30 October 2015
                30 October 2015
                2015
                : 15
                : 283
                Affiliations
                [ ]KK Research Centre, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899 Singapore
                [ ]Paediatrics Academic Clinical Programme, SingHealth Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore
                [ ]Department of Psychological Medicine, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899 Singapore
                Article
                720
                10.1186/s12884-015-0720-z
                4628323
                26518448
                9d325b85-9c1d-45b1-ad29-c12865ed8630
                © Tan et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 26 January 2015
                : 23 October 2015
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Obstetrics & Gynecology
                genetic association,family history,menstrual period regularity,perinatal depression,pregnancy

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