An autoimmune disease causing fluctuating muscle weakness, and one where genetics turned out to split cleanly by age of onset: the risk locus found in early-onset cases showed no association at all in a later study restricted to people diagnosed after 50.
Myasthenia gravis (MG) is an autoimmune disease in which antibodies attack the connection between nerve and muscle, causing fluctuating weakness that characteristically worsens with activity and improves with rest -- often first noticed in the eyes (drooping eyelids, double vision) before spreading more widely. It is rare, but well understood immunologically, which made it a good candidate for genome-wide study.
The first study behind this page examined 649 North European early-onset MG cases, finding that risk mapped most strongly to HLA-B*08 and to a specific coding change in TNIP1 (Pro151Ala) -- the finding is right in the paper's own title. rs3130544, catalogued here in the MHC class I region, reflects that finding.
A second, later study restricted specifically to late-onset MG -- 532 cases diagnosed at age 50 or older, antibody-positive, against 2,128 controls -- confirmed an earlier TNFRSF11A association, found a new genome-wide-significant locus in ZBTB10, and identified three independent HLA associations of its own. rs111945767, catalogued here in the MHC class II region, reflects this late-onset-specific finding. Tellingly, the early-onset study's TNIP1 signal showed no association at all in this late-onset cohort -- direct evidence that early-onset and late-onset MG, despite sharing a name and a clinical picture, are genetically distinct diseases rather than two severities of one disease.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 3 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Braun A et al. 2024, Nature communications rs2853986 (near RNU6-283P), rs1264706 (near TRIM31-AS1) — PMID:39537604
Chia R et al. 2022, Proceedings of the National Academy of Sciences of the United States of America rs3093958 (LINC01149) — PMID:35074870
Myasthenia gravis is diagnosed by a combination of clinical exam, a blood test for acetylcholine-receptor (or related) antibodies, and electrophysiological testing -- not by genotype. It is treated with acetylcholinesterase inhibitors, immunosuppressive therapy, and in some cases thymectomy or newer targeted biologics, managed by a neurologist.
Age of onset changes the genetics, not just the age. The variant most relevant to a case depends on whether it is early- or late-onset MG -- the two studies behind this page found substantially different loci, and one confirmed the other's main early-onset signal does not apply to late-onset cases at all.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Myasthenia Gravis comes down to these specific, well-studied positions — not a diagnosis.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 2 of 5 linked studies with a resolved discovery ancestry.
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Myasthenia Gravis. MyGeneLog™. https://www.mygenelog.com/conditions/myasthenia-gravis
No. The two studies behind this page found substantially different risk loci, and the late-onset study specifically found no association at all for the early-onset study's main TNIP1 signal -- real evidence the two are genetically distinct, despite the shared name and clinical picture.
No. Diagnosis relies on antibody blood tests and electrophysiological testing, not genotype -- and neither variant here predicts an individual's course.
With acetylcholinesterase inhibitors, immunosuppressive therapy, and in some cases thymectomy or targeted biologics, managed by a neurologist.
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