A disorder of bone remodelling running too fast and too disorganised in one or a few spots. This page holds one newly found locus and one the same research group had already identified in an earlier study — a gene osteoclasts need to develop at all.
Bone is not static. Throughout life, cells called osteoclasts break down old bone and cells called osteoblasts build new bone in its place, in a continuous, tightly controlled cycle. In Paget's disease of bone, that cycle runs too fast and too disorganised in one or a few areas of the skeleton — commonly the pelvis, spine, skull or long bones — leaving bone that is enlarged, structurally weaker, and prone to deformity, pain and fracture despite looking dense on an X-ray.
The paper behind this page is a sequel to earlier work by the same research group. They had already identified variants near CSF1, OPTN and TNFRSF11A as risk factors for Paget's disease in a previous genome-wide association study. This 2011 study extended the search and, in 2,215 cases and 4,370 controls drawn from seven independent populations, found three genuinely new loci — near PML, RIN3 and NUP205 — while also reconfirming the earlier finding at CSF1 in this larger, independent dataset. Together, the seven loci from both studies explain roughly 13% of the familial risk of the disease.
This page holds one of the new loci and the earlier, reconfirmed one side by side, and says which is which rather than presenting both as new: rs10498635 near RIN3 (odds ratio 1.44) is from the new set; rs10494112 near CSF1 is the one the group had already found and this study confirmed again.
CSF1 encodes colony-stimulating factor 1, a growth factor that osteoclasts — the bone-breaking-down cells at the centre of this disease — require to develop from their precursor cells at all. A gene that makes the signal osteoclasts depend on, found in a disease defined by osteoclasts working too fast, is about as direct a mechanism as genetics produces. It is also the oldest and most repeatedly confirmed finding on this page, which is a form of evidence in its own right: a signal that keeps reappearing across independent studies is harder to dismiss as chance than one seen once.
Paget's disease is often found incidentally — on an X-ray or a blood test showing raised alkaline phosphatase, an enzyme released by overactive bone remodelling, done for an unrelated reason. Many people have no symptoms at all. When treatment is needed, it is with bisphosphonates, drugs that slow the overactive bone breakdown directly; genotype plays no role in that decision.
What actually gets this looked for. Bone pain, especially in the pelvis, spine or a long bone; a bone that appears bowed or enlarged; or hearing loss from skull involvement are what typically prompt an X-ray or blood test. Nothing on this page detects the disease, and nothing here should delay that evaluation.
Paget's disease clusters in families more than chance would predict, and roughly 13% of that familial clustering is explained by the seven common loci found across both of this group's studies — a meaningful fraction, but most of the familial risk remains unaccounted for by known common variants. A separate, rare and much more direct cause exists too: mutations in SQSTM1 cause a high-penetrance, dominantly inherited form of the disease in some families, which is a different genetic question from the common variants on this page.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Paget's Disease of Bone comes down to these specific, well-studied positions — not a diagnosis.
Databases, guidelines and references
No. The two variants here each shift risk by a fraction and neither detects the disease. It is usually found on an X-ray or a blood test for alkaline phosphatase, often for an unrelated reason.
That is worth raising with a doctor, since a rare SQSTM1 mutation causes a dominantly inherited, high-penetrance form of the disease in some families — a different and more direct question than the common variants on this page.
Because the paper does. It found three genuinely new loci and, separately, re-tested an earlier finding (CSF1) in a larger set of cases. Presenting both as equally new would misstate what the study actually did.
CSF1 makes a growth factor that osteoclasts — the bone-breaking-down cells this disease is a disorder of — need to develop at all. A gene that makes that signal turning up in a disease of overactive osteoclasts is a mechanism, not just a statistical association, and it is also the finding that has been confirmed most times.
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