Faculty Collaboration Database

Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis. J Bone Miner Res 2006 Mar;21(3):424-37

Date

02/24/2006

Pubmed ID

16491291

DOI

10.1359/JBMR.051202

Scopus ID

2-s2.0-33644541419 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

UNLABELLED: A genome-wide screen was conducted using a large white 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, 20q12 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.

Author List

Xiong DH, Shen H, Xiao P, Guo YF, Long JR, Zhao LJ, Liu YZ, Deng HY, Li JL, Recker RR, Deng HW

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Bone Density
Epistasis, Genetic
Female
Femur Neck
Genetic Linkage
Genome, Human
Genomics
Humans
Male
Middle Aged
Osteoporosis
Quantitative Trait Loci
Risk Factors
Sex Factors