Dataset Information

Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD.

ABSTRACT: Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome-wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for systematic GxE interaction analysis in MDD in subjects of European ancestry to date. Most of the known candidate genes/variants could not be supported. Thus, their impact on GxE interaction in MDD may be questionable. Our results underscore the need for larger samples, more extensive assessment of environmental exposures, and greater efforts to investigate new methodological approaches in GxE models for MDD.

SUBMITTER: Van der Auwera S

PROVIDER: S-EPMC5726923 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD.

Van der Auwera Sandra S Peyrot Wouter J WJ Milaneschi Yuri Y Hertel Johannes J Baune Bernhard B Breen Gerome G Byrne Enda E Dunn Erin C EC Fisher Helen H Homuth Georg G Levinson Douglas D Lewis Cathryn C Mills Natalie N Mullins Niamh N Nauck Matthias M Pistis Giorgio G Preisig Martin M Rietschel Marcella M Ripke Stephan S Sullivan Patrick P Teumer Alexander A Völzke Henry H Boomsma Dorret I DI Wray Naomi R NR Penninx Brenda B Grabe Hans H

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20171121 1

Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impac ...[more]

PMID: 29159863

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Project description:BackgroundMajor depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone.MethodsThe RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology-Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained.DiscussionThe RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role.Trial registrationThe trial protocol has been registered 01-02-2022 on ClinicalTrials.gov with ID "NCT05217758".

Dataset Information

Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD.

Publications

Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD.

Similar Datasets

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