Proximal hip geometry is linked to several chromosomal regions: Genome-wide linkage results from the Framingham Osteoporosis Study

Demissie, Serkalem; Dupuis, Josée; Cupples, L. Adrienne; Beck, Thomas; Kiel, Douglas P.; Karasik, David

doi:10.1016/j.bone.2006.09.020

Cited by 51 publications

(55 citation statements)

References 65 publications

(65 reference statements)

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“…Although none of these suggestive linkages confirmed previous reports, five linkages (at 1p35.5, 1p36, 2p11.2, 4q11 and 6q22-23) were reported in the Framingham population with different but related phenotypes [21,22]. For example, at 1p35.5, our linkage was with NN_ID whereas the previous report was for NN_OD.…”

Section: Discussionsupporting

confidence: 73%

“…For example, at 1p35.5, our linkage was with NN_ID whereas the previous report was for NN_OD. Although not identical, these phenotypes are related in that NN_OD is composed of NN_ID plus 2 times cortical thickness [21]. Similarly, our linkage at 4q11 was for S_Z, whereas the previous report was for NN_Z [21], both related to bending strength but at different areas of the proximal femur.…”

Section: Discussionsupporting

confidence: 45%

“…Although not identical, these phenotypes are related in that NN_OD is composed of NN_ID plus 2 times cortical thickness [21]. Similarly, our linkage at 4q11 was for S_Z, whereas the previous report was for NN_Z [21], both related to bending strength but at different areas of the proximal femur. Among our suggestive linkages reported here, those at chromosomes 1p36 and 14q23 were previously reported by us as being suggestive regions of linkage for femoral neck BMD [24].…”

Section: Discussionsupporting

confidence: 45%

“…There is growing evidence to support the importance of heredity on geometric components of bone strength, including suggestive linkages to quantitative trait loci influencing proximal femur geometry in reports of genome-wide linkage analysis from three different research groups [17][18][19][20][21]32]. In the most recent of these reports, the same HSA methods were used as in the current report [21,22].…”

Section: Introductionmentioning

confidence: 92%

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Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

Streeten

Beck

O’Connell

et al. 2008

Bone

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Introduction-Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis Program (HSA) and performed autosomewide linkage analysis of hip geometric structural phenotypes.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 45%

Section: Discussionsupporting

confidence: 45%

Section: Introductionmentioning

confidence: 92%

See 2 more Smart Citations

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

Streeten

Beck

O’Connell

et al. 2008

Bone

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“…(31,32) In brief, the FOS original and the offspring cohorts represent members of two-generational (mostly nuclear) families recruited at different times. Descriptions of the family samples with musculoskeletal phenotypes available for analyses in the FOS are provided elsewhere, (32,33) as well as being available publicly through the dbGaP at http://view.ncbi.nlm.nih.gov/dbgap. For this study, a sample of 2211 women and 1633 men who had phenotypic measurements and who consented to genetic analyses was available.…”

Section: Samplementioning

confidence: 99%

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

Gupta

Cheung

Hsu

et al. 2011

Journal of Bone and Mineral Research

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Genome-wide association studies (GWAS) using high-density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single-nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene-set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes-SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP-phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross-sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene-set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis-related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk. ß

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A genome wide linkage scan of metacarpal size and geometry in the Framingham Study

Karasik

Shimabuku

Zhou

et al. 2008

American J Hum Biol

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Bone geometry is a significant component of bone strength, and has a clinical utility in predicting fractures and quantifying bone loss. Bone geometry is known to have a substantial genetic component. We performed linkage analysis to identify chromosomal regions governing metacarpal bone geometry. A genome-wide scan (with a set of 615 markers with spacing of approximately 5.7 cM) was performed on 1,702 individuals from 330 extended families of the Framingham Study. Midshaft width was measured and several indices calculated, namely Metacarpal Cortical Thickness (MCT), Cortical Index (MCI), and Section Modulus (MZ), using digitized X-rays of 1,380 participants (men, n = 666, mean age 55.2 yr, women, n = 714, 55.5 yr). Metacarpals 2, 3, and 4 were averaged. Heritability was significant for all indices, ranging from 0.51 to 0.72. Linkage analysis of indices adjusted for age, age(2), and estrogen status in women, identified chromosomal regions 6p21, 9p21, 11q21-q22, and Xq26-Xq27, with LOD scores >2.0. Additional adjustment for smoking, height, and BMI, generally reduced the LOD scores. Finally, bivariate linkage analysis confirmed that a QTL on chr. 6 (51 cM) was shared by midshaft width and MZ (LOD = 2.40, adjusted for all covariates). Neither MCT nor MCI shared linkage loci with width or MZ. In conclusion, we have identified chromosomal regions potentially linked to bone geometry. Genes in these regions may regulate bone geometry via effects on body size. Identification and subsequent characterization of loci for bone geometry can further elucidate the genetic contributions to bone's resistance to stress.

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Proximal hip geometry is linked to several chromosomal regions: Genome-wide linkage results from the Framingham Osteoporosis Study

Abstract: INTRODUCTION-Femoral geometry contributes to bone strength and predicts hip fracture risk. The purpose of this study was to evaluate heritability (h 2 ) of geometric indices of the proximal hip and to perform whole-genome linkage analyses of these traits, adjusted for body size.

Cited by 51 publications

References 65 publications

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

A genome wide linkage scan of metacarpal size and geometry in the Framingham Study

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