Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia.
School of Biomedical Sciences, University of Western Australia, Crawley, Australia.
J Bone Miner Res. 2018 Jun;33(6):1044-1051. doi: 10.1002/jbmr.3412. Epub 2018 Mar 24.
Osteoporosis is a complex disease with a strong genetic component. Genomewide association studies (GWAS) have been very successful at identifying common genetic variants associated with bone parameters. A recently published study documented the results of the largest GWAS for bone mineral density (BMD) performed to date (n = 142,487), identifying 307 conditionally independent single-nucleotide polymorphisms (SNPs) as associated with estimated BMD (eBMD) at the genomewide significance level. The vast majority of these variants are non-coding SNPs. Expression quantitative trait locus (eQTL) studies using disease-specific cell types have increasingly been integrated with the results from GWAS to identify genes through which the observed GWAS associations are likely mediated. We generated a unique human osteoclast-specific eQTL data set using cells differentiated in vitro from 158 participants. We then used this resource to characterize the 307 recently identified BMD GWAS SNPs for association with nearby genes (±500 kb). After correction for multiple testing, 24 variants were found to be significantly associated with the expression of 32 genes in the osteoclast-like cells. Bioinformatics analysis suggested that these variants and those in strong linkage disequilibrium with them are enriched in regulatory regions. Several of the eQTL associations identified are relevant to genes that present strongly as having a role in bone, particularly IQGAP1, CYP19A1, CTNNB1, and COL6A3. Supporting evidence for many of the associations was obtained from publicly available eQTL data sets. We have also generated strong evidence for the presence of a regulatory region on chromosome 15q21.2 relevant to both the GLDN and CYP19A1 genes. In conclusion, we have generated a unique osteoclast-specific eQTL resource and have used this to identify 32 eQTL associations for recently identified BMD GWAS loci, which should inform functional studies of osteoclast biology. © 2018 American Society for Bone and Mineral Research.
骨质疏松症是一种具有强烈遗传成分的复杂疾病。全基因组关联研究（GWAS）非常成功地鉴定了与骨参数相关的常见遗传变异。最近发表的一项研究记录了迄今为止进行的最大的骨密度（BMD）全基因组关联研究（GWAS）的结果（n = 142487），确定了 307 个条件独立的单核苷酸多态性（SNP）与全基因组显著水平的估计骨密度（eBMD）相关。这些变体绝大多数是非编码 SNP。使用特定于疾病的细胞类型进行的表达数量性状基因座（eQTL）研究已越来越多地与 GWAS 的结果相结合，以通过观察到的 GWAS 关联可能介导的基因进行鉴定。我们使用来自 158 名参与者的体外分化的细胞生成了一个独特的人类破骨细胞特异性 eQTL 数据集。然后，我们使用该资源对最近鉴定的 307 个 BMD GWAS SNP 与附近基因（±500 kb）进行关联进行特征描述。在进行多重测试校正后，发现 24 个变体与破骨细胞样细胞中 32 个基因的表达显著相关。生物信息学分析表明，这些变体及其与它们强连锁不平衡的变体在调节区域中富集。鉴定出的一些 eQTL 关联与那些在骨骼中具有强烈作用的基因相关，特别是 IQGAP1、CYP19A1、CTNNB1 和 COL6A3。从公开可用的 eQTL 数据集中获得了许多关联的支持证据。我们还为与 GLDN 和 CYP19A1 基因都相关的 15q21.2 染色体上的调节区域的存在提供了强有力的证据。总之，我们生成了一个独特的破骨细胞特异性 eQTL 资源，并利用该资源鉴定了最近鉴定的 307 个 BMD GWAS 基因座的 32 个 eQTL 关联，这应该为破骨细胞生物学的功能研究提供信息。 © 2018 美国骨骼与矿物质研究协会。
