title: Genetic analysis of high bone mass cases from the BARCOS cohort of Spanish postmenopausal women.
abstract: The aims of the study were to establish the prevalence of high bone mass (HBM) in a cohort of Spanish postmenopausal women (BARCOS) and to assess the contribution of LRP5 and DKK1 mutations and of common bone mineral density (BMD) variants to a HBM phenotype. Furthermore, we describe the expression of several osteoblast-specific and Wnt-pathway genes in primary osteoblasts from two HBM cases. A 0.6% of individuals (10/1600) displayed Z-scores in the HBM range (sum Z-score >4). While no mutation in the relevant exons of LRP5 was detected, a rare missense change in DKK1 was found (p.Y74F), which cosegregated with the phenotype in a small pedigree. Fifty-five BMD SNPs from Estrada et al. [NatGenet 44:491-501,2012] were genotyped in the HBM cases to obtain risk scores for each individual. In this small group of samples, Z-scores were found inversely related to risk scores, suggestive of a polygenic etiology. There was a single exception, which may be explained by a rare penetrant genetic variant, counterbalancing the additive effect of the risk alleles. The expression analysis in primary osteoblasts from two HBM cases and five controls suggested that IL6R, DLX3, TWIST1 and PPARG are negatively related to Z-score. One HBM case presented with high levels of RUNX2, while the other displayed very low SOX6. In conclusion, we provide evidence of lack of LRP5 mutations and of a putative HBM-causing mutation in DKK1. Additionally, we present SNP genotyping and expression results that suggest additive effects of several genes for HBM.
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sarrión
authors.affiliation: Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mellibovsky
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Urreizti
authors.affiliation: Departament d'Estadística, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Civit
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Cols
authors.affiliation: Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Natàlia
authors.initials: N
authors.lastname: García-Giralt
authors.affiliation: Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Guy
authors.initials: G
authors.lastname: Yoskovitz
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Aranguren
authors.affiliation: Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Malouf
authors.affiliation: Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain; CETIR Medical Imaging Centre, Barcelona, Spain.
authors.forename: Silvana
authors.initials: S
authors.lastname: Di Gregorio
authors.affiliation: Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain; CETIR Medical Imaging Centre, Barcelona, Spain.
authors.forename: Luís Del
authors.initials: LD
authors.lastname: Río
authors.affiliation: Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Güerri
authors.affiliation: Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Nogués
authors.affiliation: Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Díez-Pérez
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Balcells
mesh_terms: D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001846:Bone Development / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000235:genetics* / Q000502:physiology*; D013030:Spain; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5
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