Study on the Genetic and Environmental Effects of Adverse Childhood Events, Mood and Anxiety Disorders, and Substance Dependence

I. Background and Significance

Adverse childhood events (ACE) often have profound effects on an individual’s mental health and substance dependence. Previous studies have shown a close relationship between ACE and mood and anxiety disorders (M/AD) as well as substance use disorders (SUD). However, whether these effects are direct or indirect and whether they are moderated by genetic risk is still unclear.

This study, published in Nature Human Behaviour, aims to explore the mechanisms by which ACE influence M/AD and SUD and to investigate the moderating role of polygenic risk scores (PRS) in this process. The researchers use modeling to analyze both direct and indirect pathways, providing a basis for individualized prevention and treatment.

II. Source of the Study

The study, led by Henry R. Kranzler, was conducted by researchers from several renowned institutions, including the University of Pennsylvania School of Medicine and Yale School of Medicine. The article was accepted on April 10, 2024, and published online in Nature Human Behaviour with DOI https://doi.org/10.1038/s41562-024-01885-w.

III. Research Process and Methods

a) Research Process

The study sample comes from the Yale-Penn cohort, including 12,668 participants, with 44.9% being female, 42.5% African American, and 42.1% European American. The study mainly includes the following steps:

1. Data Preprocessing and Variable Construction:

   • Constructing latent variables for ACE, M/AD, and SUD.
   • Analyzing M/AD and SUD factors using polygenic risk scores (PRS).

2. Model Building and Analysis:

   • Constructing and comparing two mediation models: the forward self-medication model and the reverse substance-induced model.
   • Analyzing these pathways using the latent variables model.

3. Detection of the Moderating Effects of Polygenic Risk Scores:

   • Detecting the moderating effects of polygenic risk scores on the pathways in the mediation models (gene × environment interactions, G×E).

Study Sample and Analysis Methods

This study includes 12,668 participants, divided into 9,695 individuals diagnosed with SUD (76.5%) and 2,973 individuals without an SUD diagnosis (23.5%). Nearly one-third (33.2%) of participants had one or more M/AD diagnoses. Various indicators of the study were mainly analyzed and constructed using latent variables and polygenic risk scores.

The latent variable for ACE includes ten variables reflecting experiences before age 13, such as family instability, violent crime, and physical abuse. These indicators are significantly associated with the latent variable and have high internal consistency (homogeneity).

The latent variable for SUD includes five DSM-IV SUD diagnoses: alcohol, cocaine, opioid, tobacco, and cannabis dependence. These five diagnoses also showed high internal consistency in the latent variable.

The latent variable for M/AD includes eight mental disorders: major depressive disorder (MDD), bipolar disorder, post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), etc. Although the association degree with the latent variable is slightly lower, it remains significant.

IV. Main Research Results

b) Main Results

The study found significant indirect paths in both mediation models, but the forward mediation effect through M/AD was stronger than the reverse mediation effect through SUD. The core comparative results are as follows:

1. Forward Model:

   • There is a significant direct association between ACE and SUD (β=0.08, p<0.001), indicating that individuals with more ACE are more likely to develop SUD.
   • Additionally, the indirect association through M/AD (β=0.05, p<0.001) explained 38% of the total association.

2. Reverse Model:

   • There is also a significant direct association between ACE and M/AD (β=0.37, p<0.001), indicating that individuals with more ACE are more likely to develop M/AD.
   • The indirect association through SUD (β=0.04, p<0.001) explained 9% of the total association.

c) Conclusion and Research Value

The study shows that adverse childhood events affect adult mood and anxiety disorders and substance dependence through multiple pathways. The concretization of these pathways can provide a basis for formulating personalized prevention and treatment plans. The study particularly emphasizes the importance of preventive interventions, recommending increased ACE screening in medical and school environments.

d) Research Highlights

1. Large Sample Size: The study includes over 12,000 participants, providing sufficient statistical power to draw clear conclusions.

2. Innovative Methods: For the first time, combining latent variable models and polygenic risk scores to analyze the relationship between ACE, mental disorders, and substance dependence.

3. Identification of Gene-Environment Interactions (G×E): The study reveals various moderating effects of polygenic risk scores on the pathways between ACE and SUD as well as M/AD.

e) Other Important Information

The study emphasizes the potential value of polygenic risk scores in predicting and preventing mental disorders and substance dependence. If these scores are accurate enough, they can be used in clinical screening and intervention.

V. Significance and Value of the Study

By revealing the complex relationship between adverse childhood events, genetic risk, and mental health issues, this study provides new theoretical and practical guidance. The research results provide the scientific community with a deeper understanding of the causes of mental health problems and offer strong support for the formulation of clinical intervention strategies. For example, targeted interventions on adverse childhood experiences may effectively reduce the risk of developing mood disorders and substance dependence in adulthood.