Hinxton, (Scicasts) — A study published today (March 2) in the American Journal of Psychiatry details the discovery of three additional genetic risk markers for depression, building on the discovery of two genetic risk factors in 2015.

Researchers at Virginia Commonwealth University, the European Bioinformatics Institute (EMBL-EBI) and Wellcome Sanger Institute have found that the contribution of genetic variations to depression may differ between people who have experienced serious adversities in their life and those who haven’t. By carrying out a genome-wide association study that took into account whether or not a person has faced a major adversity in their life, the scientists were able to identify contributing molecular mechanisms that not previously been associated with depression.

More than 300 million people around the world have depression. While the illnesses is caused by the complex interaction of biological, social and psychological factors, little is known about the contribution of genetics to the condition. To seek to uncover the role a person's genome plays in predisposition to major depression, an international collaboration collected data from more 10,000 Han Chinese women from 50 hospitals across China as part of the China, Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) project.

In 2015, the project's collaborators published a study in Nature that revealed the first two genetic regions that are associated with an increased risk for developing major depression. The findings of this new study take the research a step further by factoring in people's life histories and discovered three additional genetic markers that only have a significant effect for people who have not experienced extreme adversity.

“We found evidence that by removing from the cohort people who have experienced major life adversities, we can unveil genetic factors associated with depression whose physiological effects may be in common to those caused by adversities. This can help researchers pin down the biological mechanisms involved in depression. This type of research should allow us to get a better understanding of the illness.

"These genes have functions in mitochondrial function and metabolism, so one potential direction for future research is to try and understand the link between depression and metabolism,” says Na Cai, joint first author on the study, and Postdoctoral Research Fellow at EMBL-EBI and Wellcome Sanger Institute.

For the purposes of the study, environmental adversity included experiences of extreme stressful life events such as childhood sexual and physical abuse.

“Identifying genetic risk variants for major depressive disorder has been difficult, likely due to associated clinical and etiological heterogeneity. Here, we highlight individual differences in clinical presentation and the importance of collecting symptom level data to tackle clinical and etiological heterogeneity in complex psychiatric traits. In order to parse the extensive heterogeneity associated with major depression, future studies will need to not only increase sample sizes, but also collect more clinical information such as major environmental adversities,” added Roseann Peterson an assistant professor at the Virginia Commonwealth University (VCU) Virginia Institute for Psychiatric and Behavioral Genetics, and a joint first author on the study.

Kenneth Kendler, and one of the study's lead researchers from the Virginia Commonwealth University (VCU), said the work could shed more light on subtypes of depression and their treatment.

“We have struggled for years using twin and family studies to try to understand how genes and environment inter-relate in causing depression. This is the first study where we have been able to do this using molecular variants. This is a potentially important advance in our understanding of this important, severe and common psychiatric disorder,” says Dr. Kenneth Kendler, professor of psychiatry and human molecular genetics in the Department of Psychiatry in the School of Medicine, Virginia Commonwealth University (VCU).

In the future it is hoped that research such as this will help to identify high-risk individuals for early intervention and personalised medicine.

“Genetic approaches, such as we have applied here, will be increasingly used to illuminate clinically relevant subtypes that will have important downstream implications for diagnosis, subtype biotyping, intervention and treatment,” added Roseann Peterson an assistant professor at the Virginia Commonwealth University (VCU) Virginia Institute for Psychiatric and Behavioral Genetics, and a joint first author on the study.

Article adapted from a Wellcome Sanger Institute news release.

Publication: Molecular genetic analysis subdivided by adversity exposure suggests etiologic heterogeneity in major depression. Peterson RE et al. American Journal of Psychiatry (2018): Click here to view.