Linkage of osteoporosis to chromosome 20p12 and association to BMP2

Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis famil...

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Published in:	PLoS biology Vol. 1; no. 3; p. E69
Main Authors:	Styrkarsdottir, Unnur, Cazier, Jean-Baptiste, Kong, Augustine, Rolfsson, Ottar, Larsen, Helene, Bjarnadottir, Emma, Johannsdottir, Vala D, Sigurdardottir, Margret S, Bagger, Yu, Christiansen, Claus, Reynisdottir, Inga, Grant, Struan F A, Jonasson, Kristjan, Frigge, Michael L, Gulcher, Jeffrey R, Sigurdsson, Gunnar, Stefansson, Kari
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01-12-2003 Public Library of Science (PLoS)
Subjects:	Alleles BMP2 gene Bone Density Bone Morphogenetic Protein 2 Bone Morphogenetic Proteins - genetics Bone Morphogenetic Proteins - physiology Chromosome 20 Chromosome Mapping Chromosomes, Human, Pair 20 Cohort Studies Fractures Genes Genetic Linkage Genetic Variation Genetics/Genomics/Gene Therapy Genotype Haplotypes Homo (Human) Humans Iceland Linkage Disequilibrium Lod Score Molecular Sequence Data Mutation, Missense Older people Osteoporosis Osteoporosis - genetics Phenotype Polymorphism, Genetic Polymorphism, Single Nucleotide Risk Factors Transforming Growth Factor beta - genetics Transforming Growth Factor beta - physiology Iceland United States > US California Haplotypes Bone Density Bone Morphogenetic Protein 2 Humans Risk Factors Molecular Sequence Data Genotype Chromosome Mapping Mutation, Missense Iceland Lod Score Linkage Disequilibrium Polymorphism, Genetic Genetic Variation Osteoporosis Phenotype Alleles Polymorphism, Single Nucleotide Bone Morphogenetic Proteins Chromosomes, Human, Pair 20 Transforming Growth Factor beta Cohort Studies Genetic Linkage
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Summary:	Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 x 10(-7)), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.0000069