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. 2003 Dec;1(3):E69.
doi: 10.1371/journal.pbio.0000069. Epub 2003 Nov 3.

Linkage of osteoporosis to chromosome 20p12 and association to BMP2

Unnur Styrkarsdottir  1 , Jean-Baptiste Cazier, Augustine Kong, Ottar Rolfsson, Helene Larsen, Emma Bjarnadottir, Vala D Johannsdottir, Margret S Sigurdardottir, Yu Bagger, Claus Christiansen, Inga Reynisdottir, Struan F A Grant, Kristjan Jonasson, Michael L Frigge, Jeffrey R Gulcher, Gunnar Sigurdsson, Kari Stefansson
Affiliations

Linkage of osteoporosis to chromosome 20p12 and association to BMP2

Unnur Styrkarsdottir et al. PLoS Biol. 2003 Dec.

Abstract

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.

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Conflict of interest statement

The authors have declared that conflicts of interest exist. Some authors have stocks in deCODE Genetics as well as equity interests. Some of the work described here is subject to patent filings for diagnostics purposes with US, J-BC, and VDJ as inventors.

Figures

Figure 1
Figure 1. Framework Linkage Scan
Framework linkage scan using 1,100 microsatellite markers for the severe (black line), moderate (red line), hip (green line), and spine (blue line) pedigree sets. The LOD score is on the y axis and the distance from the pter in Kosambi cM is on the x axis. Note that the LOD score scales are the same for all chromosomes except Chromosome 20.
Figure 2
Figure 2. The Chromosome 20p12 Linkage Region
(A) Chromosome 20 linkage scan for the narrower definition of osteoporosis (severe). The LOD score is on the y axis and the distance from pter in Kosambi cM is on the x axis. (B) Region under the linkage peak is shown in more detail, including location of microsatellite markers (STRs), location of SNPs, and location of genes in the region and their direction of transcription. The legend bar indicates the distance corresponding to 100 kb.
Figure 3
Figure 3. Association Analysis in the Focused Region
Association results for one to four consecutive microsatellite markers over the 1.7 Mb region. Only haplotypes with RRs over 1 are plotted. p Values are given on the left and megabase (Mb) locations at bottom.
Figure 4
Figure 4. BMP2 Haplotype Region and LD
(A) The location of haplotypes, markers, and the Ser37Ala missense variant is shown in relation to the location of BMP2 exons and to the LD blocks in (B). (B) Two measures of LD are shown: D′ values on the upper-left side of the plot and p values on the lower-right side. Scales for the LD strength are provided for both measures to the right. This graph shows uniformly distributed SNPs in a 370 kb region in and around the BMP2 gene. The BMP2 block and the next block downstream represent 53 kb.
See this image and copyright information in PMC

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