Genetics of HPA Axis
The HPA axis is the central stress response system, regulating cortisol production in response to physiological and psychological stressors. HPA axis dysregulation — including hypocortisolism — is consistently documented in ME/CFS and Long COVID.
This page is for educational and informational purposes only. Not a diagnostic tool. Always consult a qualified healthcare provider.
What is HPA Axis?
The hypothalamic-pituitary-adrenal (HPA) axis coordinates the body's response to stress through a cascade: hypothalamic CRH stimulates pituitary ACTH release, which drives adrenal cortisol production. Cortisol is the primary glucocorticoid, with wide-ranging effects on immune function, metabolism, and energy mobilisation. In ME/CFS and Long COVID, HPA axis hypofunction — characterised by blunted cortisol responses, reduced cortisol awakening response, and hypocortisolism — has been documented. Genetic variants in CRH, CRH receptors, glucocorticoid receptor (NR3C1), and FKBP5 (a glucocorticoid receptor co-chaperone) may influence HPA axis sensitivity and stress resilience.
Biological pathways commonly discussed in relation to HPA Axis
Research into Hypothalamic-Pituitary-Adrenal Axis and Stress Response has highlighted several biological pathways that may be relevant. Genetic variants within these pathways may influence individual susceptibility, symptom severity, or the trajectory of the condition.
Crh Acth Cortisol
CRH from the hypothalamus stimulates ACTH from the pituitary, which drives cortisol synthesis in the adrenal cortex. Variants in CRH, CRHR1, and POMC affect the upstream drive of the HPA cascade.
Glucocorticoid Receptor
NR3C1 encodes the glucocorticoid receptor (GR), which mediates cellular cortisol responses. Variants affecting GR expression or ligand binding alter cortisol sensitivity in immune and neural cells.
Fkbp5 Regulation
FKBP5 regulates glucocorticoid receptor sensitivity through a negative feedback loop. The rs1360780 variant creates an epigenetic risk for sustained HPA axis dysregulation following stress, particularly with early life adversity.
Cortisol Metabolism
HSD11B1 interconverts active cortisol and inactive cortisone in tissues. Variants affecting HSD11B1 activity alter local cortisol availability in tissues such as adipose, liver, and brain.
Key genes studied in relation to HPA Axis
The following genes have been studied in relation to Hypothalamic-Pituitary-Adrenal Axis and Stress Response. These genes span the biological pathways most commonly discussed in this area of research.
9 genes total studied in relation to HPA Axis across the ChronicDNA dataset.
Genetic variants commonly discussed
The following genetic variants (SNPs) are found in genes that have been studied in relation to HPA Axis. Each variant represents a position in the genome where individuals may carry different alleles.
22 variants total across genes studied in relation to HPA Axis.
How personal DNA data may provide educational insights
Consumer DNA files from 23andMe, AncestryDNA, and MyHeritage contain raw SNP data. When you upload your file to ChronicDNA, the analysis engine checks your genotype against a curated panel of 80+ genes selected for their relevance to Long COVID, ME/CFS, and connected biological pathways - some of which may relate to areas such as HPA Axis.
This is not a diagnostic service. Genetic variants do not determine whether you have HPA Axis, nor do they predict your clinical outcomes. The report is educational - it explains which variants you carry, what the research says about them, and how they fit into the biological pathways most relevant to chronic illness. All results should be discussed with a qualified healthcare provider.
Related conditions and pathways
HPA Axis shares biological pathways and genetic associations with the following related conditions and areas of research.
Frequently asked questions
What is the HPA axis and why is it relevant to ME/CFS and Long COVID?
The HPA axis regulates the body's stress response through cortisol. In ME/CFS and Long COVID, HPA axis hypofunction — reduced cortisol production and blunted stress responses — has been documented, potentially contributing to fatigue, immune dysregulation, and impaired resilience to physiological stressors.
What is FKBP5 and why is it discussed in chronic illness?
FKBP5 is a glucocorticoid receptor co-chaperone that regulates cortisol sensitivity. The rs1360780 variant is associated with HPA axis dysregulation and has been studied in relation to stress-related conditions including PTSD, depression, and ME/CFS. It may amplify the impact of stress on HPA axis programming.
Which HPA axis genes are most studied?
Key genes include NR3C1 (glucocorticoid receptor), FKBP5, CRH, CRHR1, POMC, ACTH, and HSD11B1. These cover the full HPA cascade from hypothalamic drive to cellular cortisol response.
Is hypocortisolism in ME/CFS genetic?
HPA axis dysregulation in ME/CFS likely results from a combination of genetic predisposition (NR3C1, FKBP5 variants) and acquired dysregulation following viral infection, chronic stress, or immune activation. It is unlikely to be purely genetic in most cases.
Explore DNA insights
If you already have DNA data from 23andMe, AncestryDNA, or MyHeritage, upload your raw file to ChronicDNA and receive a personalised educational report covering genes studied in relation to HPA Axis and connected biological pathways.
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9 genes · 22 variants analysed in relation to HPA Axis