title: Targeted sequencing of the Paget's disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget's disease of bone.
abstract: Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by increased but disorganized bone remodelling. Previous genome-wide association studies identified a locus on chromosome 14q32 tagged by rs10498635 which was significantly associated with susceptibility to PDB in several European populations. Here we conducted fine-mapping and targeted sequencing of the candidate locus to identify possible functional variants. Imputation in 741 PDB patients and 2699 controls confirmed that the association was confined to a 60 kb region in the RIN3 gene and conditional analysis adjusting for rs10498635 identified no new independent signals. Sequencing of the RIN3 gene identified a common missense variant (p.R279C) that was strongly associated with the disease (OR = 0.64; P = 1.4 × 10(-9)), and was in strong linkage disequilibrium with rs10498635. A further 13 rare missense variants were identified, seven of which were novel and detected only in PDB cases. When combined, these rare variants were over-represented in cases compared with controls (OR = 3.72; P = 8.9 × 10(-10)). Most rare variants were located in a region that encodes a proline-rich, intrinsically disordered domain of the protein and many were predicted to be pathogenic. RIN3 was expressed in bone tissue and its expression level was ∼10-fold higher in osteoclasts compared with osteoblasts. We conclude that susceptibility to PDB at the 14q32 locus is mediated by a combination of common and rare coding variants in RIN3 and suggest that RIN3 may contribute to PDB susceptibility by affecting osteoclast function.
authors.affiliation: Rheumatology and Bone Disease Section, Centre for Genomic & Experimental Medicine.
authors.forename: Mahéva
authors.initials: M
authors.lastname: Vallet
authors.affiliation: MRC Human Genetics Unit and Centre for Genomic & Experimental Medicine and.
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.affiliation: Rheumatology and Bone Disease Section, Centre for Genomic & Experimental Medicine.
authors.forename: Sachin
authors.initials: S
authors.lastname: Wani
authors.affiliation: Rheumatology and Bone Disease Section, Centre for Genomic & Experimental Medicine.
authors.forename: Antonia
authors.initials: A
authors.lastname: Sophocleous
authors.affiliation: South East Scotland Clinical Genetics Service, Centre for Genomic & Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Warner
authors.affiliation: Rheumatology and Bone Disease Section, Centre for Genomic & Experimental Medicine.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Salter
authors.affiliation: Rheumatology and Bone Disease Section, Centre for Genomic & Experimental Medicine.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.affiliation: Rheumatology and Bone Disease Section, Centre for Genomic & Experimental Medicine omar.albagha@igmm.ed.ac.uk.
authors.forename: Omar M E
authors.initials: OM
authors.lastname: Albagha
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D004252:DNA Mutational Analysis; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D020125:Mutation, Missense; D010001:Osteitis Deformans / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C487967:RIN3 protein, human