CACNA1C rs1006737, Threatening Life Events, and Gene–Environment Interaction Predict Major Depressive Disorder

BackgroundMajor depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.MethodThe RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.ResultsPRS significantly predicted depression, explaining 1.1% of variance in phenotype (p= 1.9 × 10−6). SLEs and CT were also associated with MDD status (p= 2.19 × 10−4andp= 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p= 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.ConclusionsCT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.

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Gene × environment interactions in the prediction of response to antidepressant treatment

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145712001459 ◽

2013 ◽

Vol 16 (3) ◽

pp. 701-711 ◽

Cited By ~ 15

Author(s):

Torsten Klengel ◽

Elisabeth B. Binder

Keyword(s):

Major Depressive Disorder ◽

Complex Traits ◽

Antidepressant Treatment ◽

Environment Interaction ◽

Major Depressive ◽

Prediction Of Response ◽

Gene Environment Interaction ◽

Genetic Disposition ◽

Health Burden ◽

Gene Environment

Abstract Major depressive disorder (MDD) is responsible for an increasing individual and global health burden. Extensive research on the genetic disposition to develop MDD and to predict the response to antidepressant treatment has yet failed to identify strong genetic effects. The concept of gene × environment interaction takes into account that environmental factors have been identified as important components in the development of MDD and combines both, genetic predisposition and environmental exposure, to elucidate complex traits such as MDD. Here, we review the current research on gene × environment interactions with regard to the development of MDD as well as response to antidepressant treatment. We hypothesize that gene × environment interactions delineate specific biological subtypes of depression and that individuals with such pathophysiological distinct types of depression will likely respond to different treatments. The elucidation of gene × environment interactions may thus not only help to understand the pathophysiology of MDD but could also provide markers for a personalized antidepressant therapy.

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The effects of the interplay of genetics and early environmental risk on the course of internalizing symptoms from late childhood through adolescence

Development and Psychopathology ◽

10.1017/s0954579415000401 ◽

2015 ◽

Vol 28 (1) ◽

pp. 225-237 ◽

Cited By ~ 6

Author(s):

Rashelle J. Musci ◽

Katherine E. Masyn ◽

Kelly Benke ◽

Brion Maher ◽

George Uhl ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Internalizing Symptoms ◽

Latent Trait ◽

Self Report ◽

Health Concern ◽

Environment Interaction ◽

Major Depressive ◽

Polygenic Score ◽

Gene Environment

AbstractInternalizing symptoms during adolescence and beyond is a major public health concern, particularly because severe symptoms can lead to the diagnosis of a number of serious psychiatric conditions. This study utilizes a unique sample with a complex statistical method in order to explore Gene × Environment interactions found in internalizing symptoms during adolescence. Data for this study were drawn from a longitudinal prevention intervention study (n = 798) of Baltimore city school children. Internalizing symptom data were collected using self-report and blood or saliva samples genotyped using Affymetrix 6.0 microarrays. A major depression polygenic score was created for each individual using information from the major depressive disorder Psychiatric Genetics Consortium and used as a predictor in a latent trait–state–occasion model. The major depressive disorder polygenic score was a significant predictor of the stable latent trait variable, which captures time-independent phenotypic variability. In addition, an early childhood stressor of death or divorce was a significant predictor of occasion-specific variables. A Gene × Environment interaction was not a significant predictor of the latent trait or occasion variables. These findings support the importance of genetics on the stable latent trait portion of internalizing symptoms across adolescence.

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Interactions Between Glycogen Synthase Kinase-3β Gene Polymorphisms, Negative Life Events, and Susceptibility to Major Depressive Disorder in a Chinese Population

Frontiers in Psychiatry ◽

10.3389/fpsyt.2020.503477 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiarun Yang ◽

Siyuan Ke ◽

Zhengxue Qiao ◽

Xiuxian Yang ◽

Xiaohui Qiu ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Life Events ◽

Glycogen Synthase ◽

Allelic Variation ◽

Negative Life Events ◽

Glycogen Synthase Kinase ◽

Environment Interaction ◽

Major Depressive ◽

Gsk 3Β

Background: Recent studies suggest that glycogen synthase kinase (GSK)-3β is involved in the development of major depressive disorder (MDD). The aim of this study was to investigate the interaction between GSK-3β polymorphism (rs6438552, rs334558, and rs2199503) and negative life events in the pathogenesis of major depressive disorder (MDD).Methods: DNA genotyping was performed on peripheral blood leukocytes in 550 patients with MDD and 552 age- and gender-matched controls. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). A chi-square method was employed to assess the gene-environment interaction (G × E).Results: Differences in rs6438552, rs334558, and rs2199503 genotype distributions were observed between MDD patients and controls. Significant G × E interactions between allelic variation of rs6438552, rs334558, and rs2199503 and negative life events were observed. Individuals with negative life events and carrying genotypes of rs6438552 A+, rs334558 A+, and rs2199503G+ have increased the risk of depression.Conclusions: These results indicate that interactions between the GSK-3β rs6438552, rs334558, and rs2199503 polymorphisms and environment increases the risk of developing MDD.

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The death(s) of close friends and family moderate genetic influences on symptoms of major depressive disorder in adolescents

Psychological Medicine ◽

10.1017/s0033291710001285 ◽

2010 ◽

Vol 41 (4) ◽

pp. 721-729 ◽

Cited By ~ 1

Author(s):

S. Gheyara ◽

K. L. Klump ◽

M. McGue ◽

W. G. Iacono ◽

S. A. Burt

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Life Events ◽

Negative Life Events ◽

Genetic Influences ◽

Phenotypic Variance ◽

Major Depressive ◽

Sibling Interaction ◽

Behavior Study ◽

Gene Environment

BackgroundPrior work has suggested that genetic influences on major depressive disorder (MDD) may be activated by the experience of negative life events. However, it is unclear whether these results persist when controlling for the possibility of confounding active gene–environment correlations (rGE).MethodWe examined a sample of 1230 adopted and biological siblings between the ages of 10 and 20 years from the Sibling Interaction and Behavior Study. MDD was measured via a lifetime DSM-IV symptom count. Number of deaths experienced served as our environmental risk experience. Because this variable is largely independent of the individual's choices/behaviors, we were able to examine gene–environment interactions while circumventing possible rGE confounds.ResultsBiometric analyses revealed pronounced linear increases in the magnitude of genetic influences on symptoms of MDD with the number of deaths experienced, such that genetic influences were estimated to be near-zero for those who had experienced no deaths but were quite large in those who had experienced two or more deaths (i.e. accounting for roughly two-thirds of the phenotypic variance). By contrast, shared and non-shared environmental influences on symptoms of MDD were not meaningfully moderated by the number of deaths experienced.ConclusionsSuch results constructively replicate prior findings of genetic moderation of depressive symptoms by negative life events, thereby suggesting that this effect is not a function of active rGE confounds. Our findings are thus consistent with the notion that exposure to specific negative life events may serve to activate genetic risk for depression during adolescence.

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Factors associated with the onset of major depressive disorder in adults with type 2 diabetes living in 12 different countries: results from the INTERPRET-DD prospective study

Epidemiology and Psychiatric Sciences ◽

10.1017/s2045796020000438 ◽

2020 ◽

Vol 29 ◽

Author(s):

C. E. Lloyd ◽

N. Sartorius ◽

H. U. Ahmed ◽

A. Alvarez ◽

S. Bahendeka ◽

...

Keyword(s):

Type 2 Diabetes ◽

Major Depressive Disorder ◽

Depressive Symptoms ◽

Depressive Disorder ◽

Life Events ◽

Stressful Life Events ◽

Regression Analyses ◽

Major Depressive

Abstract Aims To examine the factors that are associated with changes in depression in people with type 2 diabetes living in 12 different countries. Methods People with type 2 diabetes treated in out-patient settings aged 18–65 years underwent a psychiatric assessment to diagnose major depressive disorder (MDD) at baseline and follow-up. At both time points, participants completed the Patient Health Questionnaire (PHQ-9), the WHO five-item Well-being scale (WHO-5) and the Problem Areas in Diabetes (PAID) scale which measures diabetes-related distress. A composite stress score (CSS) (the occurrence of stressful life events and their reported degree of ‘upset’) between baseline and follow-up was calculated. Demographic data and medical record information were collected. Separate regression analyses were conducted with MDD and PHQ-9 scores as the dependent variables. Results In total, there were 7.4% (120) incident cases of MDD with 81.5% (1317) continuing to remain free of a diagnosis of MDD. Univariate analyses demonstrated that those with MDD were more likely to be female, less likely to be physically active, more likely to have diabetes complications at baseline and have higher CSS. Mean scores for the WHO-5, PAID and PHQ-9 were poorer in those with incident MDD compared with those who had never had a diagnosis of MDD. Regression analyses demonstrated that higher PHQ-9, lower WHO-5 scores and greater CSS were significant predictors of incident MDD. Significant predictors of PHQ-9 were baseline PHQ-9 score, WHO-5, PAID and CSS. Conclusion This study demonstrates the importance of psychosocial factors in addition to physiological variables in the development of depressive symptoms and incident MDD in people with type 2 diabetes. Stressful life events, depressive symptoms and diabetes-related distress all play a significant role which has implications for practice. A more holistic approach to care, which recognises the interplay of these psychosocial factors, may help to mitigate their impact on diabetes self-management as well as MDD, thus early screening and treatment for symptoms is recommended.

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