Gene-Environment Interactions, Major Depressive Disorder and Traumatic Experiences

Post by Lincoln Tracy 

What's the science?

Depression is one of the most common mental illnesses in the world and Major Depressive Disorder, or MDD, is the most common clinically recognized form of depression. Previous research has identified that environmental factors influence the risk of developing MDD. For example, MDD is more commonly seen in people who report being exposed to stressful life events and trauma when they were younger. Twin studies have shown that there is also a heritable genetic component to MDD. Data from genome-wide association studies (GWAS) – a way of examining hundreds of thousands of genetic markers across a set of DNA – can be used to estimate how common genetic variants contribute to this genetic predisposition. Few studies have focused on the genetic components of trauma and how this might affect depression. Further, there is evidence to suggest that reported trauma is heritable. This week in Molecular Psychiatry, Coleman and colleagues sought to assess the relationship between genetic variance, the risk for MDD, and reported exposure to trauma in a single large cohort. To do so, the authors used data from the UK Biobank, an international health resource that follows the health and well-being of more than half a million volunteer participants.  

How did they do it?

The UK Biobank has assessed approximately half a million British individuals aged between 40 and 70 for a range of health-related phenotypes and biological measures, including GWAS data. A subset of these individuals has completed additional questionnaires assessing common mental health disorders – including MDD – and exposure to traumatic events. After excluding individuals who also self-reported other psychiatric conditions such as schizophrenia, the authors were left with a sample of 92,957 participants for whom they had both genetic and questionnaire data. Individuals were grouped based on their questionnaire responses; first on whether they reported having MDD or not, then on whether they reported previously experiencing a traumatic event or not. This allowed the authors to perform three sets of analyses comparing individuals with MDD to controls; comparing all individuals regardless of previous trauma exposure, comparing only individuals who reported previous trauma exposure, and comparing individuals with no history of trauma exposure. Individuals were first compared across demographic variables and common factors associated with MDD such as sex, age, and socioeconomic status. The GWAS data were used to identify individual genetic variants associated with MDD. The authors then combined the GWAS results to assess what proportion of the variability was associated with single nucleotide polymorphism (SNP) heritability. Finally, the authors calculated genetic correlations to determine the shared genetic influences between individuals with MDD and other groups. 

What did they find?

First, the authors found that 36% of individuals had been exposed to an MDD-related trauma. A greater proportion of individuals with MDD (45%) had been exposed to an MDD-related trauma compared to individuals without MDD (17%). Individuals with MDD were more commonly female, younger, came from a lower socioeconomic background, and had a higher BMI than individuals without MDD. These differences between individuals with and without MDD were also observed when the authors analyzed data only for individuals with a history of exposure to trauma, as well as when they analyzed the data for individuals without an exposure to trauma. Second, they found that the SNP-based heritability of MDD was greater in individuals who reported a history of traumatic exposure compared to without such a history. The heritability of MDD was 24% in individuals with a history of traumatic exposure, and only 12% in those without such a history. The authors also performed simulations with the genetic data to demonstrate that heritability was not confounded by the genetic correlations between MDD and previous traumatic exposure. This suggests that the combined effect of the genetic variations associated with MDD are greater in people reporting traumatic exposure. Finally, they found that waist circumference was significantly associated with MDD – but only in individuals who reported exposure to trauma, not individuals without a history of trauma. No significant associations with other factors (e.g., body mass index or years of education completed) were observed.

What's the impact?

This study used the largest single cohort to date to investigate the relationship between MDD and self-reported exposure to trauma. It displays that, within the UK Biobank, the genetic associations with MDD vary depending on the context. Specifically, it shows that the genetic heritability of MDD is larger in individuals with a history of traumatic exposure. This, together with the other findings, imply that the contribution of genetic variants to the observed variance in MDD is greater when additional risk factors are present. Further studies are required to examine whether similar associations are observed in non-European populations. 

Coleman et al. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank. Molecular Psychiatry (2020). Access the original scientific publication here.