title: Fine mapping of bone structure and strength QTLs in heterogeneous stock rat.
abstract: We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3×10(-6)). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3 Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis.
authors: Medicine, Indiana University School of Medicine, IN, USA. Electronic address: ialam@iu.edu.
authors: Imranul
authors: I
authors: Alam
authors: Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA.
authors: Daniel L
authors: DL
authors: Koller
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Toni
authors: T
authors: Cañete
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Gloria
authors: G
authors: Blázquez
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Carme
authors: C
authors: Mont-Cardona
authors: Wellcome Trust Center for Human Genetics, Oxford OX3 7BN, United Kingdom.
authors: Regina
authors: R
authors: López-Aumatell
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Esther
authors: E
authors: Martínez-Membrives
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Sira
authors: S
authors: Díaz-Morán
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Adolf
authors: A
authors: Tobeña
authors: Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Alberto
authors: A
authors: Fernández-Teruel
authors: Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunolgy Unit, Karolinska Institutet, S171 76 Stockholm, Sweden.
authors: Pernilla
authors: P
authors: Stridh
authors: Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunolgy Unit, Karolinska Institutet, S171 76 Stockholm, Sweden.
authors: Margarita
authors: M
authors: Diez
authors: Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunolgy Unit, Karolinska Institutet, S171 76 Stockholm, Sweden.
authors: Tomas
authors: T
authors: Olsson
authors: Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunolgy Unit, Karolinska Institutet, S171 76 Stockholm, Sweden.
authors: Martina
authors: M
authors: Johannesson
authors: Wellcome Trust Center for Human Genetics, Oxford OX3 7BN, United Kingdom.
authors: Amelie
authors: A
authors: Baud
authors: Medicine, Indiana University School of Medicine, IN, USA; Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA.
authors: Michael J
authors: MJ
authors: Econs
authors: Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA.
authors: Tatiana
authors: T
authors: Foroud
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000502:physiology*; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000502:physiology*; D008040:Genetic Linkage; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D006706:Homeostasis; D015810:Linkage Disequilibrium; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000502:physiology*; D008297:Male; D015588:Observer Variation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051381:Rats
keywords: Bone strength; Bone structure; Genes; Heterogeneous stock rat; Osteoporosis