Non-coding RNA expression and exposure to childhood adversity: a systematic review of the human literature

Introduction

Exposure to childhood adversity is associated with lasting social, psychological and neurobiological adaptations, and is a major risk factor for adverse mental and physical health outcomes. The underlying biological mechanisms are only partially understood. ncRNAs are increasingly being studied as epigenetic mediators of gene expression. Differential expression, particularly of miRNAs, has been implicated in a range of psychiatric conditions.

Aims

This systematic review aimed to 1) identify, appraise and synthesise existing literature on ncRNA expression in humans exposed to childhood adversity; 2) characterise types of ncRNA studied; 3) identify consistently differentially expressed ncRNAs in this context and 4) examine associations with psychiatric conditions.

Methods

A systematic review was conducted in accordance with PRISMA guidelines. PubMed, PsycINFO, Embase and Web of Science were searched. Any study reporting ncRNA differential expression or association with childhood adversity in humans prior to age 18 was included. Data were extracted and synthesised using a vote-counting approach, recording the number of analyses in which each ncRNA was differentially expressed or associated with childhood adversity and the direction of effect.

Results

Twenty studies met inclusion criteria with thirteen included psychiatric samples. miRNAs were by far the predominant class of ncRNA, examined in 19 studies. Two studies examined broader ncRNAs, including ribosomal rsRNAs, tsRNAs, Y RNAs and lncRNAs.

A tendency towards downregulation or negative associations of miRNAs with childhood adversity was observed, with miR-103a-3p and miR-107 reported as consistently downregulated or negatively associated with adversity in three and five analyses across two and three studies respectively. The miR-34/449 family was downregulated or negatively associated across 10 analyses over four studies, although one analysis demonstrated miR-34b-3p was upregulated. Additionally, the let-7 family, most notably let-7g-5p, was negatively associated with adversity consistently in in two studies. However, several miRNAs showed inconsistent directions across studies, for example, miR-223-3p, miR-30b-5p and miR-30c-5p were consistently associated with adversity across various analyses in two studies, however the direction of effect was inconsistent.

Associations between miRNAs and various psychiatric conditions in relation to childhood adversity were reported, though limited. Depression was studied most frequently: miR-34a was associated with depression severity, miR-9 with major depressive disorder and prefrontal-limbic connectivity, and miR-450-a-2-3p was identified as a mediator of the relationship between childhood trauma and depression. Additionally, in schizophrenia miR-125b-1-3p was downregulated in those exposed to childhood trauma. However, these were each only demonstrated in a single study.

Conclusions

This systematic review provides evidence that childhood adversity is associated with differential ncRNA expression. Most work has focused on miRNAs, with limited research into other ncRNAs. While individual miRNA findings were heterogeneous and often lacked replication, a general trend of reduced expression was observed across regulatory families, including the miR-34/449 and let-7 families in addition to miR-103a-3p and miR-107. No conclusions can be made on the relationship between ncRNA expression, psychiatric outcomes and childhood adversity exposure due to lack of replicated results. Future research should prioritise larger cohorts, comparing clinical and general populations, standardisation of methodology and broader ncRNA profiling.

References

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