Genome wide association study identifies seven loci that account for 86% of the population attributable risk of Paget's disease of bone

Albagha, Omar, Fraser, William, Gennari, Luigi, Hooper, Michael, Van Hul, Wim, Isaia, Gianluca, Nicholson, Geoff, Papapoulos, Socrates, Montes, Javier del Pino, Gonzalez-Sarmiento, Rogelio, di Stefano, Marco, Wani, Sachin, Walsh, John, Ralston, Stuart for the GDPD Consortium, Visconti, Micaela, Alonso, Nerea, Goodman, Kristeen, Brandi, Maria Luisa, Cundy, Tim, Dargie, Rosemary and Falchetti, Alberto (2011). Genome wide association study identifies seven loci that account for 86% of the population attributable risk of Paget's disease of bone. In: 1stIOF-ESCEO Pre-Clinical Symposium Oral Communication Abstracts. 1st IOF-ESCEO Pre-Clinical Symposium, Valencia, Spain, (12-12). 23-26 March 2011. doi:10.1007/s00198-011-1564-7

Author Albagha, Omar
Fraser, William
Gennari, Luigi
Hooper, Michael
Van Hul, Wim
Isaia, Gianluca
Nicholson, Geoff
Papapoulos, Socrates
Montes, Javier del Pino
Gonzalez-Sarmiento, Rogelio
di Stefano, Marco
Wani, Sachin
Walsh, John
Ralston, Stuart for the GDPD Consortium
Visconti, Micaela
Alonso, Nerea
Goodman, Kristeen
Brandi, Maria Luisa
Cundy, Tim
Dargie, Rosemary
Falchetti, Alberto
Title of paper Genome wide association study identifies seven loci that account for 86% of the population attributable risk of Paget's disease of bone
Conference name 1st IOF-ESCEO Pre-Clinical Symposium
Conference location Valencia, Spain
Conference dates 23-26 March 2011
Proceedings title 1stIOF-ESCEO Pre-Clinical Symposium Oral Communication Abstracts   Check publisher's open access policy
Journal name Osteoporosis International   Check publisher's open access policy
Place of Publication Surrey, United Kingdom
Publisher Springer
Publication Year 2011
Sub-type Published abstract
DOI 10.1007/s00198-011-1564-7
ISSN 0937-941X
Volume 22
Issue Supp. 1
Start page 12
End page 12
Total pages 1
Collection year 2012
Language eng
Formatted Abstract/Summary
Objectives: Paget’s disease of bone (PDB) is a common disorder with strong genetic component that affects up to 2% of Caucasians aged 55 years and above. Genetic factors are important in PDB but so far SQSTM1 is the only gene that has been confirmed to cause classical PDB. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome wide association study (Albagha et al., 2010, Nat Genet). The aim of this study was to identify additional susceptibility genes using an extended genomewide association study.

Materials/Methods: We analysed 290,115 SNPs from a discovery sample of 741 PDB patients without SQSTM1 mutations and 2,699 controls from the Wellcome trust case control consortium. This is followed by a replication of the top 27 SNPs identified from the discovery stage in replication cohorts which consisted of 1,474 PDB cases from six different geographic regions and 1,671 unaffected controls. Association testing was performed using standard allelic χ2 statistics and data from replication cohorts were analysed using standard meta-analysis methods.

We confirmed our previously reported association with variants at CSF1 (rs10494112; P=7.06×10−35), OPTN (rs1561570; P=4.37×10−38), and TNFRSF11A (rs3018362; P=7.98×10−21; OR=1.45) and identified four additional PDB susceptibility loci on 8q22 (P=7.38×10−17); 15q24 (P=1.6×10−14); 14q32 (P=2.55×10−11) and 7q33 (P= 8.45×10−10). The seven susceptibility loci were found to account for 86% of the population attributable risk of PDB with a 50-fold difference in risk between carriers of protective and susceptibility alleles.

We have identified seven loci that contribute substantially to PDB susceptibility and this study provides new insights into the genetic architecture of PDB. Further work is now required to define the molecular mechanisms responsible for these associations and to determine if predictive genetic testing for these susceptibility alleles might be of clinical value in identifying patients at risk of the disease or complications.
Q-Index Code CX
Q-Index Status Provisional Code
Institutional Status UQ

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