Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada.
Nat Genet. 2023 Aug;55(8):1277-1287. doi: 10.1038/s41588-023-01444-5. Epub 2023 Aug 9.
In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P < 3.6 × 10). These genes were highly enriched for a set of known causal genes for osteoporosis (65-fold; P = 2.5 × 10). Exome-wide significant genes had 96-fold increased odds of being the top ranked effector gene at a given GWAS locus (P = 1.8 × 10). By integrating proteomics Mendelian randomization evidence, we prioritized CD109 (cluster of differentiation 109) as a gene for which heterozygous loss of function is associated with higher bone density. CRISPR-Cas9 editing of CD109 in SaOS-2 osteoblast-like cell lines showed that partial CD109 knockdown led to increased mineralization. This study demonstrates that the convergence of common and rare variants, proteomics and CRISPR can highlight new bone biology to guide therapeutic development.
在这项研究中，我们利用罕见编码变异和常见等位基因的综合证据，确定了骨质疏松症的治疗靶点。我们进行了一项大规模的多民族外显子组全基因组关联研究，以评估骨矿物质密度，结果表明，19 个基因中的罕见编码等位基因负担与估计的骨矿物质密度相关（P<3.6×10）。这些基因在一组已知的骨质疏松症因果基因中高度富集（65 倍；P=2.5×10）。在外显子组全基因组显著的基因中，在给定的 GWAS 基因座处，成为排名最高的效应基因的可能性增加了 96 倍（P=1.8×10）。通过整合蛋白质组学孟德尔随机化证据，我们将 CD109（分化簇 109）作为一个基因进行优先排序，杂合性功能丧失与更高的骨密度相关。CRISPR-Cas9 编辑 SaOS-2 成骨样细胞系中的 CD109 表明，部分 CD109 敲低导致矿化增加。这项研究表明，常见和罕见变异、蛋白质组学和 CRISPR 的融合可以突出新的骨生物学，以指导治疗的发展。
