Major depressive disorder (MDD) affects more than 300 million people globally, is the leading cause of disability and is a major contributor to the overall burden of disease. Unfortunately, it is also the one of the most scientifically mysterious illnesses out of all the psychiatric disorders. According to the American Psychiatric Association,
“Depression (major depressive disorder) is a common and serious medical illness that negatively affects how you feel, the way you think and how you act. Depression causes feelings of sadness and/or a loss of interest in activities once enjoyed. It can lead to a variety of emotional and physical problems and can decrease a person’s ability to function at work and at home.”
As the study of cognitive disorder advances, research groups have tried many different methods of studying MDD. MDD is highly heritable and children who have depressed parents are at a higher risk of developing MDD. In more recent years, a mixture of environmental and genetic factors has been associated with the development of MDD. 
However, the mixture of environmental and genetic factors have only proven to predict MDD in part. According to Humphreys et al. from Vanderbilt University and the University of British Columbia, epigenetic markers will prove to be stronger predictors of the development of MDD than just genes alone. 
Epigenetics and depression
Multiple studies have found a variety of different HPA-axis gene sites (HPA-axis is our central stress response system that is characterized by hypothalamic release of corticotropin by the corticotropin-releasing hormone) contribute to depression. To name a few,
- CRHR1 gene (also known as the Corticotropin Releasing Hormone Receptor 1 gene). This gene encodes a G-protein coupled receptor that corticotropin releasing the cortisol hormone. This protein regulates diverse physiological processes such as stress.  
- CRHR2 gene (also known as the Corticotropin Releasing Hormone Receptor 2 gene), has been associated with stress sensitivity and anxious behaviour. However, their psychiatric phenotypes are weaker than CRHR1. 
- NR3C1 gene (also known as Nuclear Receptor Subfamily 3 Group C Member 1 gene) has been associated with both the pathophysiology of depression and elevated cortisol and psychotic symptoms in MDD. 
Scientists have found that DNA methylation (an epigenetic modification) at these HPA-axis specific gene sites have been linked to alter the function of the HPA-axis-mediated stress response.
“DNA methylation (DNAm) is responsive to environmental input and has been shown to interact with genetic variation to predict brain and behavioural outcomes; thus, DNAm of HPA-axis genes may be an important signature of the biological impact of environmental exposures on the stress response system.”
The HPA-axis system can be disrupted not only by individuals with MDD but also by those who are at an elevated risk for developing MDD. Therefore, the DNAm of loci within the HPA axis may be the key to early prediction of MDD.
Can DNAm within HPA-axis genes predict MDD?
Humphreys et al.’s main mission was to determine whether DNA methylation within HPA-axis specific genes can predict the subsequent onset of MDD. They collected saliva samples from 77 adolescent girls from 9 to 14 years old (using Oragene·DNA) who were at familial risk for depression. None of the participants were diagnosed with MDD, but were recruited on the basis of being at high or low familial risk for depression based on their mother’s history of MDD.
The saliva DNA samples were genotyped for 59 single-nucleotide polymorphisms (SNPs) across CpG sites for HPA-axis specific genes NR3C1, NR3C2, CRH, CRHR2, and FKBP5. They found about 7 CpG sites that significantly predict the onset of MDD in NR3C1, CRH, CHR1, and CRHR2.
“Methylation levels continued to be a significant predictor of the onset of MDD and additional CpG sites were identified as significantly associated with MDD, suggesting that non-inherited factors (e.g., environmental factors) predict the onset of MDD through variation in levels of DNAm over and above the effects of genetic variation and familial risk. These data indicate that there are likely both genetic and epigenetic contributions to depression risk, but because of modifiability of DNAm, epigenetic markers may be more useful independent predictor of MDD risk.”
Saliva DNA (according to Braun et al.,) has a better correlation to the brain than blood or buccal cells, making it the preferable sample type when studying disorders of the brain (such as MDD) with DNAm. You can learn more from our blog, Genome-wide DNA methylation comparisons: Brain tissue vs. blood, saliva and buccal cells .
This study by Humphreys et al. provides a link between epigenetic variation and the biological by-products of HPA-axis activity, such as cortisol production in response to stress. This link has been proven to provide a more accurate, early prediction in MDD than just genes alone.
Related blogs: Genome-wide DNA methylation comparison: Brain tissue vs. blood, saliva and buccal cells
 Humphreys et al. DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis. Translational Psychiatry. 9:245 (2019).