From genetics to systems biology of stress-related mental disorders

Abstract

Many individuals will be exposed to some form of traumatic stress in their lifetime which, in turn, increases the likelihood of developing stress-related disorders such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD) and anxiety disorders (ANX). The development of these disorders is also influenced by genetics and have heritability estimates ranging between ∼30 and 70%. In this review, we provide an overview of the findings of genome-wide association studies for PTSD, depression and ANX, and we observe a clear genetic overlap between these three diagnostic categories. We go on to highlight the results from transcriptomic and epigenomic studies, and, given the multifactorial nature of stress-related disorders, we provide an overview of the gene-environment studies that have been conducted to date. Finally, we discuss systems biology approaches that are now seeing wider utility in determining a more holistic view of these complex disorders.

Differences in Genetic Correlations between Posttraumatic Stress Disorder and Alcohol Use Disorder-Related Phenotypes Compared to Alcohol Consumption-Related Phenotypes

“…In terms of the post-hoc enrichment analyses, the finding that for EAs, the GWAS that reached FDR significance all met for brain tissues, but not others, is generally consistent with prior work for PTSD and other neuropsychiatric traits (Dalvie et al, 2021; Gelernter et al, 2019). However, additional work is needed to better understand why only three of the GWAS (MVP PTSD Re-Experiencing, DPW GSCAN, DPW UKB) exceeded the FDR cut-off.…”

“…In terms of the post-hoc enrichment analyses, the finding that for EAs, the GWAS that reached FDR significance all met for brain tissues, but not others, is generally consistent with prior work for PTSD and other neuropsychiatric traits (Dalvie et al, 2021;Gelernter et al, 2019).…”

Mineralocorticoid receptor and glucocorticoid receptor work alone and together in cell-type-specific manner: Implications for resilience prediction and targeted therapy

“…The shared traits were centered around heart and thyroid diseases. For stress-related mental disorders, TWAS-based GTAs have been identified for glucocorticoid regulated genes and pathways ( Dalvie et al, 2021 ; Gelernter et al, 2019 ; Huckins et al, 2020 ; Stein et al, 2021 ).…”

“…Taken together, stress-related psychopathology arises from differences at various levels of gene regulation in diverse brain cell types that converge on specific pathways (e.g., GC signaling) potentially harboring clinical significance ( Dalvie et al, 2021 ). Adopting the three-hit concept of stress susceptibility ( Daskalakis et al, 2013a ), the interaction of genetic factors (hit-1) with early-life environmental factors (hit-2) precipitates in altered cell-type-specific glucocorticoid signaling that is mediated by epigenetic modifications, which in turn program brain plasticity with consequences for susceptibility (resilience or vulnerability) to later-life environment (hit-3).…”

Involvement of a BH3-only apoptosis sensitizer gene Blm-s in hippocampus-mediated mood control

“…Mood disorders such as depression and anxiety are common public health problems with a lifetime prevalence of 4–29%, and both rank among the top ten causes of disability [ 1 , 2 ]. Mood disorders are heterogeneous diseases, involving multiple factors, including neural circuits, neuromodulators, immune function, and genetic factors [ 3 – 7 ]. The mood is governed by distributed brain circuitry, which includes the hippocampus, amygdala, hypothalamus-pituitary axis, ventral tegmental area, nucleus accumbens, habenula, and medial prefrontal cortex [ 8 ].…”