Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

Albagha, Omar; Visconti, M.; Alonso, Nerea; Langston, Anne L; Cundy, Tim; Dargie, Rosemary; Dunlop, Malcolm; Fraser, William D.; Hooper, Michael J.; Isaia, Gianluca; Nicholson, Geoffrey C.; Montes, Javier del Pino; González‐Sarmiento, Rogelio; Stefano, Marco Di; Tenesa, Albert; Walsh, John P.; Ralston, Stuart H.

doi:10.1038/ng.562

Cited by 261 publications

(233 citation statements)

References 43 publications

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“…Three SNPs (rs1561570, rs825411, and rs2095388), all located within a 30-kb region, were analyzed in both stages of the study, and the strongest signal was observed for SNP rs1561570. (20) These findings were replicated in a larger cohort of PDB patients from different countries. (21) OPTN, a candidate gene located in this region, negatively regulates TNFa-induced NF-kB activation, and a putative NF-kB binding site has been identified in the OPTN promoter.…”

Section: Discussionmentioning

confidence: 66%

“…Conversely, nonparametric analyses revealed most suggestive linkage on chromosomes 10 (Zmax ¼ 6,2 at 20 to 30 Mbp from 10pter) and 8 (Zmax ¼ 6,2 at 120 Mb). Given the consistency of the former association with some previous studies in SQSTM1-negative patients, (19)(20)(21) we performed a genetic screening of the OPTN and CSF1 gene loci (see above), but we failed to identify any causative mutation at both the genomic and transcription levels.…”

Section: Genetic Analysismentioning

confidence: 67%

“…(19) More recently, a genome-wide association study in 750 sporadic PDB cases without SQSTM1 mutations and 1002 controls identified three candidate disease loci, replicated in an independent set of 500 cases and 535 controls. (20) One of these loci was located on chromosome 10p13. Three SNPs (rs1561570, rs825411, and rs2095388), all located within a 30-kb region, were analyzed in both stages of the study, and the strongest signal was observed for SNP rs1561570.…”

Section: Discussionmentioning

confidence: 99%

“…(21) OPTN, a candidate gene located in this region, negatively regulates TNFa-induced NF-kB activation, and a putative NF-kB binding site has been identified in the OPTN promoter. (20) We identified a second interesting locus on chromosome 8, near TNFRSF11B gene (encoding OPG), the gene associated with juvenile PDB (JPD; OMIM 239000). (23,24) This association was suggested by both parametric and nonparametric analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA of four affected patients was specifically amplified using several sets of primers designed to amplify each of the coding exons of all five genes and was analyzed by direct sequencing. Given the results from linkage analysis in SQSTM1-negative PDB familes (19) and of two genome-wide association studies (20,21) suggesting a possible susceptibility locus in 10p13 within a region encoding for optineurin (OPTN) and an additional locus next to the CSF1 gene, we also searched for possible OPTN or CSF1 mutations in affected members of our pedigree.…”

Section: Candidate Gene Analysismentioning

confidence: 99%

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Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Gianfrancesco¹,

Rendina²,

Merlotti³

et al. 2012

Journal of Bone and Mineral Research

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Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. ß

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Section: Discussionmentioning

confidence: 66%

Section: Genetic Analysismentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Candidate Gene Analysismentioning

confidence: 99%

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Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Gianfrancesco¹,

Rendina²,

Merlotti³

et al. 2012

Journal of Bone and Mineral Research

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<emph type="ital">SQSTM1</emph> Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Fecto¹

2011

Arch Neurol

586

410

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SQSTM1Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

et al. 2013

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IMPORTANCE Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING Primary care or referral center. PARTICIPANTS An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

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Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

Cited by 261 publications

References 43 publications

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

<emph type="ital">SQSTM1</emph> Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

SQSTM1Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

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