Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis

Dong Hai Xiong, Hui Shen, Peng Xiao, Yan Fang Guo, Ji Rong Long, Lan Juan Zhao, Yao Zhong Liu, Hong Yi Deng, Jin Long Li, Robert R. Recker, Hong Wen Deng

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

A genome-wide screen was conducted using a large while sample to identify QTLs for FNCS geometry. We found significant linkage of FNCS parameters to 20q12 and Xq25, plus significant epistatic interactions and sex-specific QTLs influencing FNCS geometry variation. Introduction: Bone geometry, a highly heritable trait, is a critical component of bone strength that significantly determines osteoporotic fracture risk. Specifically, femoral neck cross-sectional (FNCS) geometry is significantly associated with hip fracture risk as well as genetic factors. However, genetic research in this respect is still in its infancy. Materials and Methods: To identify the underlying genomic regions influencing FNCS variables, we performed a remarkably large-scale whole genome linkage scan involving 3998 individuals from 434 pedigrees for four FNCS geometry parameters, namely buckling ratio (BR), cross-sectional area (CSA), cortical thickness (CT), and section modulus (Z). The major statistical approach adopted is the variance component method implemented in SOLAR. Results: Significant linkage evidence (threshold LOD = 3.72 after correction for tests of multiple phenotypes) was found in the regions of 20q12 and Xq25 for CT (LOD = 4.28 and 3.90, respectively). We also identified eight suggestive linkage signals (threshold LOD = 2.31 after correction for multiple tests) for the respective geometry traits. The above findings were supported by principal component linkage analysis. Of them, 20ql2 was of particular interest because it was linked to multiple FNCS geometry traits and significantly interacted with five other genomic loci to influence CSA variation. The effects of 20q12 on FNCS geometry were present in both male and female subgroups. Subgroup analysis also revealed the presence of sex-specific quantitative trait loci (QTLs) for FNCS traits in the regions such as 2p14, 3q26, 7q21 and 15q21. Conclusions: Our findings laid a foundation for further replication and fine-mapping studies as well as for positional and functional candidate gene studies, aiming at eventually finding the causal genetic variants and hidden mechanisms concerning FNCS geometry variation and the associated hip fractures.

Original languageEnglish
Pages (from-to)424-437
Number of pages14
JournalJournal of Bone and Mineral Research
Volume21
Issue number3
DOIs
StatePublished - Mar 2006

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Quantitative Trait Loci
Femur Neck
Osteoporosis
Genome
Hip Fractures
Bone and Bones
Genetic Research
Osteoporotic Fractures
Pedigree
Principal Component Analysis
Phenotype

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis. / Xiong, Dong Hai; Shen, Hui; Xiao, Peng; Guo, Yan Fang; Long, Ji Rong; Zhao, Lan Juan; Liu, Yao Zhong; Deng, Hong Yi; Li, Jin Long; Recker, Robert R.; Deng, Hong Wen.

In: Journal of Bone and Mineral Research, Vol. 21, No. 3, 03.2006, p. 424-437.

Research output: Contribution to journalArticle

Xiong, Dong Hai ; Shen, Hui ; Xiao, Peng ; Guo, Yan Fang ; Long, Ji Rong ; Zhao, Lan Juan ; Liu, Yao Zhong ; Deng, Hong Yi ; Li, Jin Long ; Recker, Robert R. ; Deng, Hong Wen. / Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis. In: Journal of Bone and Mineral Research. 2006 ; Vol. 21, No. 3. pp. 424-437.
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abstract = "A genome-wide screen was conducted using a large while sample to identify QTLs for FNCS geometry. We found significant linkage of FNCS parameters to 20q12 and Xq25, plus significant epistatic interactions and sex-specific QTLs influencing FNCS geometry variation. Introduction: Bone geometry, a highly heritable trait, is a critical component of bone strength that significantly determines osteoporotic fracture risk. Specifically, femoral neck cross-sectional (FNCS) geometry is significantly associated with hip fracture risk as well as genetic factors. However, genetic research in this respect is still in its infancy. Materials and Methods: To identify the underlying genomic regions influencing FNCS variables, we performed a remarkably large-scale whole genome linkage scan involving 3998 individuals from 434 pedigrees for four FNCS geometry parameters, namely buckling ratio (BR), cross-sectional area (CSA), cortical thickness (CT), and section modulus (Z). The major statistical approach adopted is the variance component method implemented in SOLAR. Results: Significant linkage evidence (threshold LOD = 3.72 after correction for tests of multiple phenotypes) was found in the regions of 20q12 and Xq25 for CT (LOD = 4.28 and 3.90, respectively). We also identified eight suggestive linkage signals (threshold LOD = 2.31 after correction for multiple tests) for the respective geometry traits. The above findings were supported by principal component linkage analysis. Of them, 20ql2 was of particular interest because it was linked to multiple FNCS geometry traits and significantly interacted with five other genomic loci to influence CSA variation. The effects of 20q12 on FNCS geometry were present in both male and female subgroups. Subgroup analysis also revealed the presence of sex-specific quantitative trait loci (QTLs) for FNCS traits in the regions such as 2p14, 3q26, 7q21 and 15q21. Conclusions: Our findings laid a foundation for further replication and fine-mapping studies as well as for positional and functional candidate gene studies, aiming at eventually finding the causal genetic variants and hidden mechanisms concerning FNCS geometry variation and the associated hip fractures.",
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AU - Xiong, Dong Hai

AU - Shen, Hui

AU - Xiao, Peng

AU - Guo, Yan Fang

AU - Long, Ji Rong

AU - Zhao, Lan Juan

AU - Liu, Yao Zhong

AU - Deng, Hong Yi

AU - Li, Jin Long

AU - Recker, Robert R.

AU - Deng, Hong Wen

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