Major Depressive Disorder May Be Linked to Early Childhood Stress

Strong evidence purposes interactions between early life stress and FKBP5 genotypes could lead to significant risk of developing major depressive disorder (MDD) or post-traumatic stress disorder (PTSD), according to the results of a recent systematic review and meta-analysis of the existing literature.

“The present study provides a comprehensive evaluation whether FKBP5 gene, which is a critical regulator of stress activity axis in the brain, confers a genetic risk factor for PTSD and MDD in the event of early life adversity,” Yogesh Dwivedi, PhD, Department of Psychiatry and Behavioral Neurobiology, University of Alabama in Birmingham, and co-author of the review and analysis said. “This is very important given that these 2 disorders are impacted heavily on early life stress.”

Previous research has shown evidence of early childhood stresses such as abuse, parental death or divorce and neglect is strongly associated with the development of MDD, PTSD, and a higher risk of suicide.

The authors write that while prior research investigated the effects of FKBP5 variants in relation to MDD, PTSD, and other disorders, there is currently no systematic review and meta-analysis examining whether variants of FKBP5 actually increase the risk of stress-related disorders.

The research team examined specific single nucleotide polymorphisms (SNPs), and included studies that included FKBP5 rs1360780, rs3800373, or rs9470080. The authors write that those particular SNPs were chosen because they were the most frequently studied for gene-environment interaction. A total of 14 studies were identified that fit the criteria.

The meta-analysis revealed that individuals who carry specific alleles for FKBP5 exposed to early-life trauma had high risks for depression or PTSD, and provided strong evidence in support of an interaction between early-life stress and FKBP5 genotype in these disorders.

The results were not especially surprising to the researchers, as they were expecting similar results based on previous studies, however, the meta-analysis confirmed these findings in a large, combined study.

The meta-analysis does have some limitations. For example, the sample size is relatively small, because there was limited data available, additionally, there were some confounding variables that the researchers could not fully exclude, and the 3 SNPs make up a haplotype block which is associated with several susceptible common variants.

“In the future, some potential and causative functional mutation or allele needs to be identified with fine mapping or targeted sequence analysis,” write the authors.

In describing the next steps of this research, Dwivedi says the team is working toward being able to use the 3 SNPs as biomarkers to predict stress-related disorders. Such a breakthrough would be a great stride toward the goal of providing individualized treatment.

“Personalized medicine is becoming reality in treating many disorders,” says Dwivedi. “Psychiatric disorders are no exception. Thus, finding genetic basis of these disorders may help diagnose and treat patients effectively.”

The full review and meta-analysis, titled “Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis,” can be found in the Journal of Affective Disorders.