Department of Epidemiology and Health Statistics, School of Public Health, Medical College of Soochow University, Jiangsu, China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, China.
J Bone Miner Res. 2019 Jun;34(6):1086-1094. doi: 10.1002/jbmr.3681. Epub 2019 Feb 28.
Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a meta-analysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (α = 5.0 × 10 ), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p = 3.58 × 10 ) and coding regions (p = 5.71 × 10 ). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations. © 2019 American Society for Bone and Mineral Research.
骨骼不同部位的骨密度（BMD）具有共同的遗传决定因素。在本研究中，我们旨在鉴定与 BMD 相关的共同基因座，对一项全基因组关联研究（GWAS）和骨骼不同部位的 BMD 荟萃分析进行联合关联研究：（i）对来自英国生物库的 142,487 名个体的脚跟 BMD 进行单一 GWAS，以及（ii）对来自骨质疏松症遗传因素（GEFOS）联盟的 66,628 名个体的全身（TB）BMD 的 30 项 GWAS 的荟萃分析。两种性状的遗传相关系数估计为 0.57。我们使用最近开发的多性状 GWAS 分析（MTAG）统计方法进行联合关联分析，以解释性状异质性和样本重叠。对多达 209,115 名个体的样本进行联合关联分析，在全基因组显著性水平（α=5.0×10 ）鉴定出 18 个与 BMD 相关的新基因座，分别解释脚跟-BMD 和 TB-BMD 遗传率的 0.43%和 0.60%。绝大多数鉴定出的先导 SNP 或其近缘物发挥局部表达数量性状基因座（cis-eQTL）活性。可信风险变体定义为位于先导 SNP 500 千碱基（kb）内且 p 值与先导 SNP 相差两个数量级的 SNP，富含转录因子结合位点（p=3.58×10 ）和编码区（p=5.71×10 ）。使用多种信息源，包括先前报道在骨生物学中起作用但未在先前 GWAS 中报道的几个基因，对这些新基因座的 56 个候选基因进行了优先级排序（PPARG、FBN2、DEF6、TNFRSF19 和 NFE2L1）。一个新鉴定的基因 SCMH1 被证明可以上调几种骨生物标志物的表达，包括碱性磷酸酶（ALP）、胶原 I（COL-I）、骨钙素（OCN）、骨桥蛋白（OPN）和 runt 相关转录因子 2（RUNX2）在小鼠成骨细胞 MC3T3-E1 细胞中，突出了其在骨形成中的调节作用。我们的结果可能为未来的功能研究提供有用的候选基因。©2019 美国骨骼与矿物质研究协会。
