&lt;italic&gt;NTRK2 &lt;/italic&gt;gene-environment interaction for predicting antidepressant response in patients with 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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

CNS Spectrums ◽

10.1017/s1092852912000430 ◽

2012 ◽

Vol 17 (2) ◽

pp. 76-86 ◽

Cited By ~ 11

Author(s):

David Mischoulon ◽

Stefania Lamon-Fava ◽

Jacob Selhub ◽

Judith Katz ◽

George I. Papakostas ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Mthfr C677t ◽

Response Rates ◽

Mthfr Gene ◽

Methionine Synthase ◽

Antidepressant Response ◽

Major Depressive ◽

Fluoxetine Treatment ◽

Intent To Treat

AbstractObjectiveTo examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response.MethodsWe screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined.ResultsPrevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C = 41%, C/T = 47%, T/T = 11%, A/A = 66%, A/G = 29%, G/G = 4%). In the fluoxetine-treated subsample (n = 49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response.ConclusionThe C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.

Download Full-text