The most common heart valve disease in older adults -- a narrowing of the aortic valve, usually from calcium buildup over decades. The largest genetic study of it to date found 241 risk loci on the autosomes and 3 more on the X chromosome, in a dataset of nearly 87,000 cases among 2.85 million people.
Aortic stenosis (AS) is a narrowing of the aortic valve, the one-way valve between the heart's main pumping chamber and the rest of the body. Most cases are late-onset and calcific -- calcium gradually builds up on a normally-formed three-leaflet valve over decades -- making it, by far, the most common heart valve disease among older adults in aging populations. A minority of cases start earlier, in people born with a bicuspid aortic valve (two leaflets instead of three); this page is about aortic stenosis as its own outcome, in people with either valve anatomy, not specifically about the bicuspid-valve pathway.
The study behind this page combined data across multiple ancestries, reaching 86,864 aortic stenosis cases among 2,853,408 individuals in total -- far larger than any earlier genetic study of the disease. It found 241 independent risk loci on the autosomes and 3 more on the X chromosome, with further sex-stratified and ancestry-stratified analyses turning up 5 additional sex-specific loci, 11 specific to European ancestry, and 1 specific to African ancestry. This catalogue currently carries 38 of these loci -- a real subset of what the paper reports, not the full set.
Among the genes near the loci catalogued here: rs17228212 sits in SMAD3, a core gene in TGF-beta signaling already linked to other aortic diseases; rs4868244 sits near NKX2-5, a transcription factor central to heart development; and rs1983931 sits in COL4A2, a collagen gene, plausible given the structural, connective-tissue nature of the valve itself. Beyond the genome-wide association results, the same study ran a transcriptome-wide analysis using gene-expression data from real aortic valve tissue, finding 54 further candidate genes, and directly tested a number of biologically promising genes with silencing experiments -- a level of follow-up validation well beyond a typical GWAS.
Before the large 2026 study above, a 2018 Icelandic study -- 2,457 cases and 349,342 controls, with follow-up in up to 4,850 further cases -- found two new loci of its own: one on chromosome 1p21 near PALMD, and rs1830321, on chromosome 2q22 in TEX41. The PALMD variant, rs7543130, is the same one already catalogued on this site's bicuspid aortic valve page -- this 2018 study found it independently, years before the paper that page cites, and reported that it associates with bicuspid aortic valve directly, not just with aortic stenosis generally. That is a real, direct genetic link between the two pages, not a coincidence of two studies naming the same gene.
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 37 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.
Small AM et al. 2026, Nature genetics rs754458 (near LTBP2), rs62139061 (near ACTR2), rs17172071 (near LINC01448), rs10481025 (COBL), rs11735005 (AFAP1), rs10417548 (near HAS1), rs2832230 (MAP3K7CL), rs744651 (near TBX4), rs113977592 (near SDK2), rs56344960 (near MIR6074), rs2071277 (NOTCH4), rs6787361 (ARHGEF26-AS1) and 25 more — PMID:41419686
Aortic stenosis is diagnosed by echocardiogram, which measures how narrowed the valve has become and how hard the heart is working against it -- not by genotype. There is currently no drug that reverses or slows the calcification itself (a point the study's authors highlight as the motivation for hunting new therapeutic targets); management is monitoring by regular echocardiogram, and valve replacement (surgical or transcatheter) once stenosis becomes severe enough to cause symptoms or strain the heart.
Not the same page as bicuspid aortic valve. A bicuspid valve is one route to developing aortic stenosis earlier in life, but most aortic stenosis occurs in people with an anatomically normal valve. See this site's separate bicuspid aortic valve page for that specific congenital condition.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Aortic Stenosis comes down to these specific, well-studied positions — not a diagnosis. 90 positions are linked to this page; the ones this page's own text discusses are shown first.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 1 of 90 linked studies with a resolved discovery ancestry.
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Aortic Stenosis. MyGeneLog™. https://www.mygenelog.com/conditions/aortic-stenosis
No. A bicuspid valve is one way to develop aortic stenosis, often earlier in life, but most aortic stenosis occurs in people with a normal three-leaflet valve that calcifies over time. See this site's separate bicuspid aortic valve page for that specific condition.
No single variant here does. The source study found 241 risk loci on the autosomes alone; this catalogue carries 38 of them, each shifting risk only modestly on its own.
By echocardiogram, and then followed with repeat imaging over time. There is currently no drug that reverses the calcification; severe cases are treated with valve replacement, surgical or transcatheter.
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