SNPwatch: Genetic Variants Associated with Risk of Paget’s Disease of Bone Identified

Aching joints and bones aren’t always just a normal part of aging.  For some, they are a symptom of Paget’s disease of bone (PDB), a condition that affects more than one million people over the age of 45 in the United States.

Bone tissue is constantly being recycled.  As old bone is broken down, new bone grows in to replace it.  In PDB, the breakdown process is sped up, so the rate of new bone generation must also increase.  This rapidly grown bone tends to be softer and weaker than normal.  In most people this doesn’t lead to any symptoms, but for some it can cause bone or joint pain, deformities or fractures.  Tingling or weakness can occur if deformed bones impinge on nerves.

The cause of PDB isn’t known, but there is thought to be a genetic component to the disease.  Between 15% and 40% of people with the disease have an affected mother, father, sibling or child, and mutations in the SQSTM1 gene have been linked to some cases.  To find the remaining genes that predispose a person to PDB, an international team led by researchers at the University of Edinburgh analyzed the DNA of close to 1,200 people with the disease and more than 1,500 controls.  Their results, published online recently in the journal Nature Genetics, identify common variations in three separate regions of the genome contribute to differences in risk of developing the disease.

The strongest genetic association for PDB was seen with rs484959.  The slightly more common C version of this SNP was linked to increased risk of the disease – each copy of a C was associated with 1.8 times odds of PDB compared to people with two Ts.  The nearby CSF1 gene is a good candidate for a gene involved in PDB susceptibility, as it is known to play a critical role in bone cell formation and survival.

An association with PDB was also seen with rs1561570.  Each copy of the somewhat more common T version of this SNP was associated with 1.5 times odds of PDB compared to people with two Cs.  The region of the genome this SNP is located in has previously been linked to familial PDB, but it is not known what gene or genes are involved.

Finally, the less common A version of rs3018362 was associated with 1.52 times odds of having PDB.  This SNP is near the gene that encodes a protein called RANK, which is important for bone cell function.  Mutations in this gene cause bone disease in both mice and humans.  SNP rs3018362 has also been associated with bone mineral density and fracture risk.

Taking into account the effects of one additional SNP in each of the three newly identified genomic regions, the researchers calculated a risk score for PDB based on a person’s number of “riskier” SNP copies.  (See table at end of post.) Individuals carrying ten or more riskier copies were found to have a sixfold increase in their risk for PDB compared to those with the median number of five.

In an interview, the study’s senior author Stuart Ralston suggested that his team’s findings could lead to a screening test for PDB.

“This is important since we know that if treatment is left too late, then irreversible damage to the bones can occur. If we were able to intervene at an early stage with preventative therapy, guided by genetic profiling, this would be a major advance,” Ralston told the BBC.

Although the SNPs described in this new study appear to account for a large portion of the genetics of PDB, the authors point out that it is likely that there are other regions of the genome that also contribute to the risk of developing the disease that were not picked up in their analysis.  They suggest that based on their success, further studies are now warranted to identify the rest of the genetic factors associated with the disease.

SNPs used in risk score calculation: SNPs mentioned above with individual odds scores are in bold.  The researchers included another nearby SNP in each genomic region in their risk score calculations.  23andMe Complete Edition customers can check their data using the links to the Browse Raw Data feature provided.

SNP Risk Version
rs484959 C
rs10494112 G
rs1561570 T
rs825411 G
rs3018362 A
rs2957128 A

Risk scores: The risk score ranges from 0-12, because a person has two copies of each of the six SNPs listed above.  A person’s risk score is determined by adding together the number of copies of risk versions (i.e. number of Cs for rs484959, number of Ts for rs1561570, etc). Odds estimates that were not statistically significant are marked with an asterisk.

Risk Score Change in Odds of PDB Compared to Average Risk Score
0,1 0.41
2 0.34
3 0.74*
4 0.83*
5 -average-
6 1.44
7 2.27
8 2.81
9 2.69
10 5.98
11, 12 6.55

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.