Preprint Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization, 2026, Wielscher et al

I used to describe PEM as a migraine-like state without the headache. Unfortunately the neurologist just looked at me like I was crazy and sent me away instead of trying to see if common migraine meds would provide any relief for feeling this way.

Migraine is a very good comparison because PEM to me involves a lot of vestibular symptoms (just looking at a simple video on Instagram will trigger instant motion sickness) which don't happen outside of PEM to me. Then there's the nausea, low appetite, slow digestion but also just feeling pain everywhere (but the head and legs for some reason), worse sleep issues than usual. But I never had any aura and the ocassional headaches I get are very mild.
My migraines are mostly of the "silent" variety (blind-spots, visual disturbance, scintillating scotoma, confusion, aphasia), sometimes there's significant pain, often not. There seems to be some connection between the migraines and ME/CFS (my collapse was precdeded by several months of increased migraine severity and frequency), but there is a strong distinction between the more acute elements of each. Even where symptoms overlap, the migraines follow a definite and consistent progression, whereas PEM seems to go up and down and come and go (to say nothing of the different durations). That said, you're absolutely right that some of vestibular symptoms, the particular nature of the motion-sickness/nausea, and sensory sensitivities can all feel very, very similar - including both the exacerbated forms that arrive with PEM and the constant forms that never really leave.
Some of the cognitive difficulties can be pretty close as well, though they are excrutiatingly difficult to describe.
 
Across 22 auxiliary traits spanning five mechanistic domains, cellular energetics, neurovascular regulation, and barrier–microbiome function showed the strongest genetic overlap with ME/CFS
That seems quite different from the MAGMA analysis on the decode results which found by far the brain to be most relevant.

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On my migraine experience and overlap with ME/CFS. I just want to say that to me I experience migraine as a symptom of ME/CFS. I never got migraines before ME/CFS. And I only ever get migraines, which are awful, during bad PEM. So for me it’s a PEM symptom plain and clear.

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I’m also wondering how much we can say migraine / IBS overlaps at the genetic level or just at the definitional level. I know personally before I got an ME diagnosis my working diagnosis was IBS. I bet a lot of ME cases end up under the IBS label. Similarly my mum has an ME/CFS like illness and her most consistent diagnosis she’s gotten since long ago when the illness started is migraine. I can imagine many ME/CFS cases who experience migraine as a main symptom of PEM may end up under that label.
 
That seems quite different from the MAGMA analysis on the decode results which found by far the brain to be most relevant.
It seems that in this study the authors pre-selected only 22 traits because they have previously been implicated in ME/CFS and the brain/synapses was not included.
We selected auxiliary traits to represent mechanistic domains repeatedly implicated in ME/CFS, including inflammation, neuroinflammation and immune dysregulation, barrier–microbiome function, vascular/perfusion control, platelet-mediated immunothrombosis, and cellular energetics
The full list is in table 1 in the online methods. Most did not reach high correlations. Migraine and IBS were already known to be correlated using the UK biobank analyses forestglip did in the DecodeME thread.

traitpaperyear Functional groupincluded in MR
T2DPMID:30297969
2018
Energy / Cellular energetics
0
nmr-Total-TriglyceridesPMID:40436851
2025
Energy / Cellular energetics
1
nmr-LactatePMID:40436851
2025
Energy / Cellular energetics
1
Mito-DNA-CNPMID:34859289
2022
Energy / Cellular energetics
1
rbc-meanPlatelet-volumePMID:32888493
2020
Immunothrombosis / Platelets
1
VWFPMID:37794186
2023
Immunothrombosis / Platelets
1
Venous-thromboembolismPMID:36777996
2022
Immunothrombosis / Platelets
0
Varicose-veinsPMID:36653477
2023
Perfusion / Vascular
0
ortho-hypotensPMID:30104761
2019
Perfusion / Vascular
1
MigranePMID:39024449
2024
Perfusion / Vascular
0
WMH-volumePMID:33293549
2020
Perfusion / Vascular
0
IBSPMID:34741163
2021
Barrier / Microbiome–epithelium
0
CrohnsPMID:37156999
2023
Barrier / Microbiome–epithelium
0
Ulcerative-colitisPMID:37156999
2023
Barrier / Microbiome–epithelium
0
AlzheimersPMID:34493870
2021
Neuroinflammation & Adaptive skew
0
MSPMID:31604244
2019
Neuroinflammation & Adaptive skew
0
Cortisol-level-1PMID:33469137
2021
Neuroinflammation & Adaptive skew
1
InsominaPMID:30804565
2019
Neuroinflammation & Adaptive skew
0
SLEPMID:36750564
2023
Neuroinflammation & Adaptive skew
0
RheumatoidArthritisPMID: 36333501
2022
Neuroinflammation & Adaptive skew
0
nmr-Glycoprotein-AcetylsPMID:40436851
2025
inflammatory
1
rbc-monoPMID:32888493
2020
inflammatory
1
 
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