Exome-wide screening identifies novel rare risk variants for bone mineral density

Summary: Bone mineral density (BMD) is an independent risk factor of osteoporosis-related fractures. We performed gene-based burden tests to assess the association between rare variants and BMD, and identified several BMD candidate genes. Purpose: BMD is highly heritable and a major predictor of osteoporotic fractures, but its genetic basis remains unclear. We aimed to identify rare risk variants contributing to BMD. Methods: Utilizing the newly released UK Biobank 200,643 exome dataset, we conducted a gene-based exome-wide association study in males and females, respectively. First, 100,639 males and 117,338 females with BMD values were included in the polygenic risk scores (PRS) analysis. Among individuals with lower 30% PRS, cases were individuals with top 10% BMD, and individuals with bottom 10% BMD were the controls. Considering the effects of vitamin D (VD), individuals with the highest 30% VD concentration were selected for VD-BMD analysis. After quality control, 741 males and 697 females were included in the BMD analysis, and 717 males and 708 females were included in the VD-BMD analysis. The variants were annotated by ANNOVAR software, then BMD and VD-BMD qualified variants were imported into the SKAT R-package to perform gene-based burden tests, respectively. Results: The gene-based burden test of the exonic variants identified genome-wide candidate associations in ANKRD18A (P = 1.60 × 10⁻⁵, P_{Bonferroni adjust} = 2.11 × 10⁻³), C22orf31 (P = 3.49 × 10⁻⁴, P_{Bonferroni adjust} = 3.17 × 10⁻²), and SPATC1L (P = 1.09 × 10⁻⁵, P_{Bonferroni adjust} = 8.80 × 10⁻³). For VD-BMD analysis, three genes were associated with BMD, such as NIPAL1 (P = 1.06 × 10⁻³, P_{Bonferroni adjust} = 3.91 × 10⁻²). Conclusions: Our study suggested that rare variants contribute to BMD, providing new sights for broadening the genetic structure of BMD.