Department of Human Genetics, McGill University, Montréal, Québec, Canada.
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Nat Genet. 2019 Feb;51(2):258-266. doi: 10.1038/s41588-018-0302-x. Epub 2018 Dec 31.
Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
骨质疏松症是一种常见的与衰老相关的疾病，主要通过骨密度（BMD）来诊断。我们评估了 426,824 个人的脚跟定量超声估计的 BMD 的遗传决定因素，确定了 518 个全基因组显著位点（301 个新位点），解释了其方差的 20%。我们在大约 120 万人中确定了 13 个与估计的 BMD（eBMD）相关的骨折部位。然后，我们从细胞特异性特征中识别出富含已知影响骨密度和强度的基因的靶基因（最大优势比（OR）= 58，P = 1×10），包括染色质构象和可及染色质位点。接下来，我们对预测靶基因中断的 126 个敲除小鼠进行了快速骨骼表型分析，与 526 个未选择的品系相比，发现异常骨骼表型的频率增加（P<0.0001）。对一个基因 DAAM2 的深入分析表明，与矿化相比，骨强度不成比例地降低。该遗传图谱为相关 SNP 与因果基因之间的联系提供了证据，为骨质疏松症的病理生理学提供了新的见解，并突出了药物开发的机会。
