Scientists have identified three new susceptibility loci for Paget disease of bone (PDB), a bone remodeling disorder that reportedly affects up to 2% of people of European ancestry. The three polymorphisms identified are within PML (at 15q24), RIN3 (at 14q32), and NUP205 (at 7q33).
Stuart H Ralston, Ph.D., Omar M E Albagha, Ph.D., and colleagues from the International Genetic Determinants of Paget’s Disease (GDPD) consortium had previously linked variants at CSF1, OPTN, and TNRSF11A with PDB based on prior work that found mutations within SQSTM1 caused a high-penetrance form of PDB.
They have now calculated that these four previously identified sites, together with the three newly identified loci, could in combination account for some 13% of the familial risk of PDB. The GDPD consortium reports its results in Nature Genetics in a paper titled “Genome-wide association identifies three new susceptibility loci for Paget’s disease of bone.”
The researchers' previous work that identified CSF1, OPTN, and TNRSF11A variants involved a genome-wide association study (GWAS) involving 692 cases and over 1,000 controls and a replication cohort of 480 cases and 520 controls.
In order to identify additional susceptibility loci, the team carried out a GWAS on an extended cohort comprising 741 cases and 2,699 controls of British descent. The results from this were confirmed by genotyping 27 of the most promising SNPs in nearly 1,474 SQSTM-1 negative cases and over 1,500 controls. The researchers in addition carried out a meta-analysis of data from the GWAS and individual replication cohorts.
This strengthened the association between PDB and the CSF1, OPTN, and TNFRSF11A loci that had previously been identified as well as highlighted the three new loci at 7q33, 14q32.12, and 15q24.1. A putative locus at 8q22.3 identified previously was also flagged in this latest research
The SNP on 7q33 most stongly implicated with PDB risk lies within the NUP205 gene, which encodes nucleoporin 205 kDa, one of the main components of the nuclear pore complex involved in the regulation of transport between the cytoplasm and nucleus, the authors report. They admit that none of the genes located within this region of DNA are known to affect bone metabolism, however, and suggest further studies will be needed to identify functional variants responsible for the PDB association.
The second new susceptibility locus, at 14q32.12, had been flagged as borderline in the consortium’s previous GWAS, but in the extended study showed significance. The 62 kb associated region is bounded by two recombination hotspots and contains RIN3, which encodes the Ras and Rab interactor 3, a protein that plays a role in vesicular trafficking through interaction with small GTPases such as Ras and Rab.
Again, the function of RIN3 in bone metabolism is unknown, although it could feasibly play a role in bone resorption, the authors point out. “It is of interest to note that mutations affecting VCP, a protein also involved in vesicular trafficking, cause the syndrome of inclusion body myopathy with early onset Paget’s disease and frontotemporal dementia.”
SNPs in the third new susceptibility locus at 15q24.1 were clustered within PML, a promyelocytic leukemia gene. The strongest signal was associated with a variant that results in a phenylalanine to leucine amino acid change in the resulting protein. PML’s role in bone metabolism is unclear, but it is known to be involved in TGF-β signaling, and TGF-β is known to play a role in the regulation of bone remodeling.
Calculations suggested that the proportion of familial risk that could be attributed to the seven loci in the replication sample was 13%, “which is much greater than that observed for other common bone diseases such as osteoporosis,” the authors note. They in addition estimated that the cumulative population attributable risk of thee loci was 86%, with the risk of PDB increasing with the increasing number of risk allele scores defined by the seven loci.
“The identified loci have relatively large effect sizes compared to other common diseases of the musculoskeletal system,” the researchers conclude. “This indicates that susceptibility to PDB is probably mediated by inheritance of a relatively small number of genes with large effect sizes as opposed to a large number of genes with small effect sizes, as seen in other complex diseases.
"Although further work will be required to identify functional variants, the present study has provided new insights into the genetic architecture of PDB and has identified several genes that were not previously suspected to play a role in bone metabolism.”