The "Autonomic-Exhaustion" Link in ME/CFS

In the preprint of (1): Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID

there is a list of "candidate core genes" which means that Single Nucleotide Polymorphisms (SNPs) within or near these genes were found to be associated with an increased risk of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS).

Here are the genes from the list "candidate core genes" most closely related to the regulation of the Autonomic Nervous System (ANS) selected by AI:

AI answer: In the 2025 neuro-metabolic model of ME/CFS, autonomic dysfunction (dysautonomia) is viewed as a failure of the Hypothalamus-Locus Coeruleus (LC) axis to maintain homeostasis. This failure manifests as POTS, orthostatic intolerance, and abnormal heart rate/blood pressure responses. 

• ABCC6: Regulates systemic mineralization and vascular elasticity; variants contribute to impaired blood flow and vascular rigidity, worsening orthostatic intolerance.

• ADTRP: Involved in vascular health and fatty acid metabolism; variants exacerbate the reduced cerebral blood flow often seen when ME/CFS patients stand up.
• ANGPT1: Critical for vascular stability and blood-brain barrier integrity; its dysfunction leads to "leaky" vessels that disrupt autonomic signaling in the brainstem.
• ANO4: A calcium-dependent channel that regulates aldosterone secretion; its impairment directly causes the fluid balance issues and low blood volume typical of ME/CFS.
• BNC2: A transcription factor essential for the development of autonomic regulatory circuits; variants can lead to a baseline "mis-wiring" of the stress-response system.
• CACNA1D: Regulates calcium influx in endocrine and brain cells; essential for the circadian and autonomic set-points managed by the hypothalamus.
• CDH12 / CDH13: Cadherins involved in cell-to-cell adhesion; essential for the physical "wiring" of the circuits that control the parasympathetic and sympathetic balance.
• KCNJ16: A potassium channel that acts as an acid-sensor in the brainstem; its dysfunction impairs the body's ability to regulate breathing and heart rate in response to metabolic changes.
• KIRREL3: Essential for the structural "wiring" of the Hypothalamus-LC axis; SNPs cause a breakdown in the communication required to maintain autonomic stability. (not on the list of "candidate core genes" - but on "the long list")
• NOS1AP: Regulates nitric oxide signaling; its dysfunction is a primary driver of impaired vasodilation, leading to the "pooling" of blood and dizziness (orthostatic intolerance).
• POPDC2: A cAMP-binding protein essential for maintaining heart-rate stability and the autonomic signals sent from the hypothalamus to the heart.
• PTPRD: Receptor-type phosphatase; its disruption impacts the thirst and appetite centers of the hypothalamus, leading to the chronic dehydration often seen in dysautonomia.
• SLC4A4: A bicarbonate transporter; its failure to regulate pH in the brain and muscles leads to the "acidic" metabolic state that triggers autonomic "crashes" after exertion.
• UNC93A: A potential ion channel regulator in the brainstem; its dysfunction impacts the electrical stability of the circuits that coordinate heart rate and blood pressure.
• YWHAB (14-3-3 beta): Acts as a scaffold for enzymes that produce norepinephrine; its deficiency causes the "norepinephrine depletion" that makes it impossible for the body to maintain blood pressure under stress.

The 2025 "Autonomic-Exhaustion" Link

These genes highlight why ME/CFS patients cannot "just push through." If genes like NOS1AP and ANO4 are not maintaining blood flow and fluid balance, and KIRREL3 has caused the brain's control center to be "mis-wired," the autonomic nervous system remains in a state of permanent crisis, unable to coordinate the complex tasks of standing, digesting, or recovering from stress

More detailed analysis 

As of late 2026, the established neuro-metabolic model of ME/CFS integrates these genes into a cohesive mechanism. In a healthy state, these proteins ensure the Autonomic Nervous System (ANS) maintains homeostasis. In the ME/CFS "vicious cycle," genetic vulnerabilities and cellular stress disrupt these systems, resulting in the characteristic "wired-but-tired" state, orthostatic instability, and metabolic failure.

1. The Architects: Structural Connectivity

In normal conditions, these proteins ensure the Hypothalamus (master controller) and Locus Coeruleus (LC) (arousal/norepinephrine center) are correctly "wired" and structurally sound.

• KIRREL3 & PTPRD:
  • Normal: These are synaptic adhesion molecules that act as the "scaffolding" for the axis. They ensure the hypothalamus can precisely signal the LC to "ramp up" for action or "dampen down" for sleep.
  • ME Disease Mechanism: SNPs in KIRREL3 or the loss of PTPRD (often seen as increased serum levels due to protein "shedding") cause synaptic instability. This leads to a "misfiring" axis where the hypothalamus cannot effectively quiet the LC at night, resulting in unrefreshing sleep and hyperarousal.

2. The Brakes: Electrical & pH Stability

These proteins act as the "electrical brakes" for autonomic neurons and the pH buffers for metabolic activity.

• KCNIP4 & ANO3/4:
  • Normal: These prevent neurons from firing too fast. KCNIP4 regulates potassium channels, while ANO3 and ANO4 are calcium-activated "reset" switches.
  • ME Disease Mechanism: SNPs weaken these "brakes." The LC neurons become hyperexcitable, firing excessively in response to minor triggers (light, sound, or stress). This chronic over-firing leads to norepinephrine depletion and severe sensory overload.
• SLC4A4 & UNC93A:
  • Normal: SLC4A4 is a bicarbonate transporter that neutralizes the acid produced during activity. UNC93A maintains the "resting electrical state" of brainstem neurons controlling breathing and heart rate.
  • ME Disease Mechanism: Impaired SLC4A4 function leads to intracellular acidification, causing metabolic fatigue in the LC and preventing the clearing of lactic acid in muscles (driving PEM). UNC93A variants cause electrical instability in the brainstem, adding to the "faulty wiring" of autonomic output.

3. The Power Grid: Vascular & Energy Management

These genes represent the vascular and metabolic support layers that sustain the ANS during physical or postural stress.

• ABCC6 & ADTRP:
  • Normal: ABCC6 prevents small vessel stiffening, while ADTRP maintains constant cerebral blood flow (CBF) regardless of body position.
  • ME Disease Mechanism: Variants cause vascular failure. Stiff vessels and an inability to maintain CBF during postural changes lead directly to Orthostatic Intolerance (OI) and "brain fog" as the LC/Hypothalamus is starved of oxygen.
• POPDC2:
  • Normal: A cAMP-sensing "switch" in the heart's pacemaker that adjusts heart rate during stress or position changes.
  • ME Disease Mechanism: Impaired binding of cAMP leads to pacemaker failure, contributing to the erratic heart rate and autonomic dysregulation seen in POTS (Postural Orthostatic Tachycardia Syndrome).
• WASF3:
  • Normal: Plays a role in cellular scaffolding under steady-state conditions.
  • ME Disease Mechanism: Induced by chronic ER stress, WASF3 disrupts mitochondrial "supercomplexes," zapping the energy supply of the LC and muscles just when needed, triggering a systemic metabolic crash and PEM.

References

1) Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID

JM Sardell, S Das, M Pearson, D Kolobkov, AR Malinowski, LM Fullwood, M Sanna, H Baxter, K McLellan, M Natt, D Lamirel, S Chowdhury, MA Strivens, S Gardner

medRxiv 2025.12.01.25341362; doi: https://doi.org/10.64898/2025.12.01.25341362

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

https://www.medrxiv.org/content/10.64898/2025.12.01.25341362v1

2) Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159; PMCID: PMC10450651.
https://pubmed.ncbi.nlm.nih.gov/37579159/