Genome-wide association with bone mass and geometry in the Framingham Heart Study

BACKGROUND:Osteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms.METHODS:We used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates [greater than or equal to]80%, HWE p [greater than or equal to] 0.001, and MAF [greater than or equal to]10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers.RESULTS:Heritability estimates for all bone phenotypes were 30-66%. LOD scores [greater than or equal to]3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679-58,934,236 bp) and 22 (35,890,398-48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 x 10-6 and 2.5 x 10-5, respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.

Tracking Human Body Pose on a Learned Smooth Space

Particle filtering is a popular method used in systems for tracking human body pose in video. One key difficulty in using particle filtering is caused by the curse of dimensionality: generally a very large number of particles is required to adequately approximate the underlying pose distribution in a high-dimensional state space. Although the number of degrees of freedom in the human body is quite large, in reality, the subset of allowable configurations in state space is generally restricted by human biomechanics, and the trajectories in this allowable subspace tend to be smooth. Therefore, a framework is proposed to learn a low-dimensional representation of the high-dimensional human poses state space. This mapping can be learned using a Gaussian Process Latent Variable Model (GPLVM) framework. One important advantage of the GPLVM framework is that both the mapping to, and mapping from the embedded space are smooth; this facilitates sampling in the low-dimensional space, and samples generated in the low-dimensional embedded space are easily mapped back into the original highdimensional space. Moreover, human body poses that are similar in the original space tend to be mapped close to each other in the embedded space; this property can be exploited when sampling in the embedded space. The proposed framework is tested in tracking 2D human body pose using a Scaled Prismatic Model. Experiments on real life video sequences demonstrate the strength of the approach. In comparison with the Multiple Hypothesis Tracking and the standard Condensation algorithm, the proposed algorithm is able to maintain tracking reliably throughout the long test sequences. It also handles singularity and self occlusion robustly.