Stress-sensitive neurosignalling in depression: an integrated network biology approach to candidate gene selection for genetic association analysis

Abstract

Genetic risk for depressive disorders is poorly understood despite consistent suggestions of a high heritable component. Most genetic studies have focused on risk associated with single variants, a strategy which has so far only yielded small (often non-replicable) risks for depressive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (polygenic risk factors). We show how knowledge of major integrated neurobiological systems provides a robust basis for defining and testing theoretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and provides a framework for a systems biology approach to candidate gene selection. We propose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stress-related behaviour. We conclude that knowledge of the neurobiology of the stress response system is likely to play a central role in future efforts to improve genetic prediction of depression and related disorders.

A systematic review and secondary data analysis of the interactions between the serotonin transporter 5-HTTLPR polymorphism and environmental and psychological factors in eating disorders

“…From a biological perspective, it is plausible that this may function via the lowered serotonin transcription associated with the s-allele of 5-HTTLPR, leading to reduced availability of a key neurotransmitter in the stress response system (van Eekelen et al, 2012). …”

Animal Approaches to Studying Risk Factors for Parkinson’s Disease: A Narrative Review

“…Another factor to be considered is that one of the main risk factors for depression is chronic stress [178]. In this respect, it has been suggested that chronic stress, by increasing nervous system susceptibility, could be a causal factor for neurodegeneration in PD [179,180].…”

Investigating Direct Links between Depression, Emotional Control, and Physical Punishment with Adolescent Drive for Thinness and Bulimic Behaviors, Including Possible Moderation by the Serotonin Transporter 5-HTTLPR Polymorphism

“…Serotonin plays a role in mood regulation, appetite, and weight ( Blundell, 1984 ; Leibowitz and Alexander, 1998 ; Kalra et al, 1999 ; Ruhé et al, 2007 ), all known to be involved in eating pathology. Serotonin is also involved in the stress-response system ( Gotlib et al, 2008 ; van Eekelen et al, 2012 ), and as 5-HTTLPR is a functional polymorphism it may conceivably play a role in EDs, directly or indirectly through interaction with other environmental stressors. However, in other fields of psychiatry, the role of 5-HTTLPR in moderating the effects of environmental stressors remains controversial; for example, in depression, where independently conducted meta-analysis continue to contradict one another (cf.…”