title: Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module.
abstract: Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Genome-wide association studies (GWAS) for BMD have identified dozens of associations; yet, the genes responsible for most associations remain elusive. Here, we used a bone co-expression network to predict causal genes at BMD GWAS loci based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. By mapping genes implicated by BMD GWAS onto a bone co-expression network, we predicted and inferred the function of causal genes for 30 of 64 GWAS loci. We experimentally confirmed that two of the genes predicted to be causal, SPTBN1 and MARK3, are potentially responsible for the effects of GWAS loci on chromosomes 2p16.2 and 14q32.32, respectively. This approach provides a roadmap for the dissection of additional BMD GWAS associations. Furthermore, it should be applicable to GWAS data for a wide range of diseases.
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Calabrese
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Larry D
authors.initials: LD
authors.lastname: Mesner
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Stains
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT 06520-8071, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Tommasini
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT 06520-8071, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Horowitz
authors.affiliation: Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Departments of Public Health Sciences and Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: crf2s@virginia.edu.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology; D002874:Chromosome Mapping / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D058866:Osteoporotic Fractures; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013049:Spectrin / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: C452439:SPTBN1 protein, human; D013049:Spectrin; C111833:MARK3 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: BMD; GWAS; bone fragility; bone mineral density; co-expression network; fracture; genetics; genome-wide association study; osteoporosis; systems genetics