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


BACKGROUND
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.


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.
Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA.
Dong-Hai
DH
Xiong
Hui
H
Shen
Peng
P
Xiao
Yan-Fang
YF
Guo
Ji-Rong
JR
Long
Lan-Juan
LJ
Zhao
Yao-Zhong
YZ
Liu
Hong-Yi
HY
Deng
Jin-Long
JL
Li
Robert R
RR
Recker
Hong-Wen
HW
Deng
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D004843:Epistasis, Genetic; D005260:Female; D005272:Femur Neck / Q000033:anatomy & histology*; D008040:Genetic Linkage; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D040641:Quantitative Trait Loci; D012307:Risk Factors; D012737:Sex Factors