Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the Chr 15 region spanning from 6 to 24cM. This region contains 131 annotated genes. Using block haplotyping, all other genes except Trps1 were eliminated as candidates for this QTL. We then examined associations of 208 SNPs within 10kb of TRPS1 with BMD and hip geometry, using human genome-wide association study (GWAS) data from the GEFOS consortium. After correction for multiple testing, six TRPS1 SNPs were significantly associated with femoral neck BMD (P=0.0015-0.0019; adjusted P=0.038-0.048). We also found that three SNPs were highly associated with femoral neck width in women (rs10505257, P=8.6×10 -5, adjusted P=2.15×10 -3; rs7002384, P=5.5×10 -4, adjusted P=01.38×10 -2). In conclusion, we demonstrated that combining association studies in humans with murine models provides an efficient strategy to identify new candidate genes for bone phenotypes.
Bibliographical noteFunding Information:
We acknowledge generous help of the GEFOS consortium in performing meta-analyses of GWAS of bone-related phenotypes in human participants. The Genetic Factors for Osteoporosis (GEFOS) consortium ( http://www.gefos.org ) has been funded by the European Commission ( HEALTH-F2-2008-201865-GEFOS ).
This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 ), NHLBI 1U01 HL066582 , and the following grants from the National Institute on Arthritis Musculoskeletal and Skin Diseases , and the National Institute on Aging : AR/AG41398 (to DPK), AR053992 (to DK), AR43618 (to WGB) and AG034019 (to CLAB). A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.
- Bone mineral density
- Hip geometry
- Human genetic association study
- Mouse models
- Trichorhinophalangeal syndrome I