RDoC and translational perspectives on the genetics of trauma‐related psychiatric disorders

Abstract

Individuals with a history of child abuse are at high risk for depression, anxiety disorders, aggressive behavior, and substance use problems. The goal of this paper is to review studies of the genetics of these stress-related psychiatric disorders. An informative subset of studies that examined candidate gene by environment (GxE) predictors of these psychiatric problems in individuals maltreated as children is reviewed, together with extant genome wide association studies (GWAS). Emerging findings on epigenetic changes associated with adverse early experiences are also reviewed. Meta-analytic support and replicated findings are evident for several genetic risk factors; however, extant research suggests the effects are pleiotropic. Genetic factors are not associated with distinct psychiatric disorders, but rather diverse clinical phenotypes. Research also suggests adverse early life experiences are associated with changes in gene expression of multiple known candidate genes, genes involved in DNA transcription and translation, and genes necessary for brain circuitry development, with changes in gene expression reported in key brain structures implicated in the pathophysiology of psychiatric and substance use disorders. The finding of pleiotropy highlights the value of using the Research Domain Criteria (RDoC) framework in future studies of the genetics of stress-related psychiatric disorders, and not trying simply to link genes to multifaceted clinical syndromes, but to more limited phenotypes that map onto distinct neural circuits. Emerging work in the field of epigenetics also suggests that translational studies that integrate numerous unbiased genome-wide approaches will help to further unravel the genetics of stress-related psychiatric disorders.

The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect

“…Clinical studies have consistently shown reduced gray matter volume, and decreased synapses and glial cells in the mPFC of patients with anxiety and mood disorders [24,25]. In addition, preclinical studies have shown that early life stress induces changes in gene expression and structural abnormalities in the mPFC [26], as well as alterations in DNA methylation in the Brain-derived neurotrophic factor ( Bdnf ) gene, reelin gene, and genes involved in the DNA methylation regulation in the mPFC [26]. Here, we found that decreased ID3 and increased GRIN1 mRNA expression in the mPFC are associated with lower depression-like behavior as evaluated in the forced swim test.…”

A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus

“…In the second stage, this set of candidate SNPs was tested in an independent sample with respect to the phenotype of interest (i.e., AUD) at a significance threshold corrected for the number of proxy-associated SNPs. Consistent with the National Institute of Mental Health’s Research Domain Criteria (RDoC) initiative, 27 – 29 we considered two-dimensional measures derived from symptom scales based on self-report information: an alcohol misuse score in the ASTARRS cohorts, and a DSM-5 AUD criterion count in the Yale-Penn cohorts. Dichotomous trauma exposure was considered as interactive factor, because it was available in both cohorts.…”

The mediating effects of childhood neglect on the association between schizotypal and autistic personality traits and depression in a non-clinical sample

“…Interestingly, recent research found that neglect (as an childhood stress) can affect gene expression, DNA transcription and translation [ 54 , 55 ], which may in turn affect some genes related to depression, as described earlier.…”