The discovery of causal genetic variants creates opportunities for new disease diagnostics and therapies. Although common-variant based genome-wide association studies (GWAS) have identified loci associated with BMD and fractures, such approache has inherent limitations. For example, it is likely unavailable to genotype/impute less common, rare mutations and structural variations that have larger effect size and might reveal unique pathways influencing bone metabolism. Previously, we reported the largest common-variant based GWAS on BMD (N=~400K). However, the identified loci only explained ~20% variance of BMD, comparing to the 85% BMD heritability estimated from twins. Thus, current common-variant based GWAS approach only detects a small fraction of genetic heritability. To fill the gap of missing heritability, whole-genome sequencing (WGS) is rapidly being incorporated into mainstream researches to provide comprehensive enumeration of human genome sequence variation. To identify novel less common and rare variants that are associated with BMD and fractures, we utilized the deep-coverage WGS (average 30X) in ~10K Caucasian participants obtained from the Amish, CHS, FHS, SAFOS and WHI studies (the NHLBI TOPMED Program) as well as ALSPAC and TWINSUK studies. We first performed gene-based collapsing association tests (allele-count and SKAT tests) to identify rare functional coding variants (MAF ≤ 0.5%) of BMD and fractures. Only loss-of-function, missense with deleterious effects and protein-altering short insertion/deletion coding variants were included. Covariates adjusted in the models included age, age2, sex, weight, height, ancestral genetic background, cohort studies and menopause status (women only). To consider potential familiar relatedness among subjects, a linear mixed-effect model with kinship/genetic relationship matrix was applied. Genome-wide significance was p < 4.27x10-6 after Bonferroni correction. The most significant association was found in IGHE gene (p=7.18x10-8) with lower LS BMD. The other novel findings included SLC26A11, ERGIC3 and STMN1 genes associated with LSBMD. No genome-wide association was found for FNBMD, but strong association (p < 6x10-5) was found in TFAP2E, CYP2B6, GDF10 and IL6 genes. Additional analyses are underway to include functional non-coding variants (e.g. variants affecting gene regulation in bone cells), which will provide a comprehensive ascertainment on sequence variants and their impact to bone health.