Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
J Bone Miner Res. 2022 Aug;37(8):1500-1510. doi: 10.1002/jbmr.4622. Epub 2022 Jul 13.
Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long noncoding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor single-nucleotide polymorphisms (SNPs) demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (false discovery rate [FDR] correction < 0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability [RCP] > 0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
骨质疏松症的特征是骨矿物质密度（BMD）低，是最常见的影响骨骼的复杂疾病，构成了主要的社会健康问题。全基因组关联研究（GWAS）已经确定了超过 1100 个影响 BMD 的关联。已经表明，长非编码 RNA（lncRNA）的扰动影响 BMD 和骨细胞的活性；然而，lncRNA 参与 BMD 的遗传调控的程度尚不清楚。在这里，我们将人类髋臼骨碎片的等位基因不平衡（AI）分析与全转录组关联研究（TWAS）和表达数量性状基因座（eQTL）colocalization 分析相结合，使用来自基因型组织表达（GTEx）项目的数据，以鉴定可能与 GWAS 关联相关的 lncRNA。我们在骨骼中鉴定了 27 个 lncRNA，它们位于接近 BMD GWAS 关联的位置，并携带表现出 AI 的单核苷酸多态性（SNP）。使用 GTEx 数据，我们通过 TWAS 鉴定了另外 31 个 lncRNA，它们的表达与 BMD 相关（错误发现率 [FDR] 校正<0.05），并且具有 colocalizing eQTL（区域 colocalization probability [RCP]>0.1）。这 58 个 lncRNA 位于 43 个 BMD 关联中。为了进一步支持鉴定的 lncRNA 具有因果作用，我们表明 58 个 lncRNA 中有 23 个随着成骨细胞分化而表达差异。我们的方法确定了可能与 BMD GWAS 关联相关的 lncRNA，并表明 lncRNA 在骨质疏松症的遗传学中发挥作用。© 2022 作者。由 Wiley 期刊公司代表美国骨骼和矿物质研究协会（ASBMR）出版的《骨骼与矿物研究杂志》发表。
