Effects of Different Stressors Are Modulated by Different Neurobiological Systems: The Role of GABA-A Versus CB1 Receptor Gene Variants in Anxiety and Depression.

Xenia Gonda,Peter Petschner,Sara Sutori,Zsofia Gal,Ian M Anderson,Gabriella Juhasz,Szabolcs Koncz,Nora Eszlari,Gyorgy Bagdy,Bill Deakin

doi:10.3389/fncel.2019.00138

Abstract

Environmental stress and its interaction with genetic variation are key contributors in the development of depression and anxiety, yet there is a failure to identify replicable genetic variants and gene-interaction effects in the background of these psychiatric symptoms. Recently it has been reported that 5-HTTLPR and NOSI interact with financial but not other types of recent stressors in the development of depression. In the present study we investigated the interaction of GABRA6 rs3219151 and CNR1 rs7766029 in interaction with different types of recent life events on the presence of depression and anxiety in a large general population sample. 2191 participants completed the List of Threatening Experiences questionnaire which covers four categories of stressful life events (financial problems, illness/personal problems, intimate relationships, and social network) experienced over the previous year and the Brief Symptom Inventory for depression and anxiety symptoms. Participants were genotyped for rs3219151 and rs7766029. Data were analyzed with linear regression models with age and gender as covariates. Results indicated that CNR1 rs7766029 interacted significantly with financial but not other types of life events both in case of depression and anxiety symptoms. In contrast, GABRA6 rs3219151 showed a significant interaction with social network related life events in case of anxiety and with illness/personal problem-related life events in case of depression. Our results suggest that the psychological impact of different types of recent stress may be differentially modulated by distinct molecular genetic pathways. Furthermore, in case of certain genetic variants, the occurring psychiatric symptom may depend on the type of stress experienced.

Highlights

In spite of the ever-increasing interest in genetic mechanisms of depression, findings in candidate gene association studies have generally not been replicated and not detected in genome-wide association studies (Flint and Kendler, 2014; Dunn et al, 2015; Gonda et al, 2018c)
The short allele of 5HTTLPR was associated with increased depressive symptoms in those exposed to recent financial stressors, but not in those exposed to any other types of recent life events
GABRA6 rs3219151 is significantly related to recent negative life events (RLEs)-illness/personal in Budapest, and CNR1 rs7766029 is significantly related to RLEsocial in Manchester

Summary

Introduction

In spite of the ever-increasing interest in genetic mechanisms of depression, findings in candidate gene association studies have generally not been replicated and not detected in genome-wide association studies (Flint and Kendler, 2014; Dunn et al, 2015; Gonda et al, 2018c). A study investigating variation in 7 genes in pathways previously implicated in the neurobiology of depression found that none influenced depressive phenotype in the absence of exposure to recent stress (Gonda et al, 2018b) In those exposed to moderate and/or severe stress, the majority of variants showed “relevance,” a Bayesian measure, to phenotype. In those aged 30 or younger the short allele showed an inverse impact on depression when exposed to social stress, reflecting a possible protective effect of this variant These results suggest that the effect of the majority of genes involved in depression may be manifested only under certain environmental settings, and different types of stressors can exert their effects via divergent genetic and neurochemical pathways. Different types of stressors should be analyzed separately in gene-environment interaction studies of depression

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