title: Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength.
abstract: Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium.
authors.affiliation: Molecular Endocrinology Group, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: J H Duncan
authors.initials: JH
authors.lastname: Bassett
authors.forename: Apostolos
authors.initials: A
authors.lastname: Gogakos
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.forename: Holly
authors.initials: H
authors.lastname: Evans
authors.forename: Richard M
authors.initials: RM
authors.lastname: Jacques
authors.forename: Anne H
authors.initials: AH
authors.lastname: van der Spek
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.forename: Edward
authors.initials: E
authors.lastname: Ryder
authors.forename: David
authors.initials: D
authors.lastname: Sunter
authors.forename: Alan
authors.initials: A
authors.lastname: Boyde
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000502:physiology; D002874:Chromosome Mapping; D017353:Gene Deletion; D057166:High-Throughput Screening Assays / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D008852:Microradiography; D064847:Multimodal Imaging; D009928:Organ Specificity; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D049268:Positron-Emission Tomography; D013718:Tensile Strength; D014057:Tomography, X-Ray Computed