Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
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DOI：
10.1016/j.bone.2013.10.015
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发表时间：
2014-02-01
期刊：
影响因子：
4.1
通讯作者：
Rivadeneira，Fernando
中科院分区：
文献类型：
--
作者：
Oei，Ling;Estrada，Karol;Rivadeneira，Fernando
脊椎骨折风险是一种可遗传的复杂特征。这项研究的目的是应用全基因组关联研究方法确定骨质疏松性椎体骨折的遗传易感因素。Gwas的发现是基于鹿特丹研究，这是一项基于人群的研究，对55岁以下的荷兰老年人进行研究；包括329例病例和2666名对照，使用放射学评分(McCloskey-Kanis)和遗传数据。通过对欧洲、美国和澳大利亚的15项独立研究和一项亚洲研究进行从头基因分型，复制了一个顶级相关的SNP。使用McCloskey-Kanis或Genant半定量定义进行椎体骨折的放射学评估。用Logistic回归模型分析SNPs与脊柱骨折的关系，并对年龄和性别进行了校正。采用固定效应、逆方差和han-Ekin交替随机效应Meta分析。全基因组的意义被设定为5×10−=8。在这项发现中，染色体16q24上的SNP(Rs11645938)与椎体骨折的风险有关。然而，在来自14项研究的5,720例病例和21,791名对照中，这种关联并不显著。固定效应Meta分析汇总估计为1.0 6(95%CI：0.98~1.14；p=0.17)，表现出高度的异质性(I2=0.5 7%；Qhetp=0.0.0006)。在HAN-ESKIN交替随机效应模型下，总和效应显著(P=0.0005)。该SNP映射到先前在GEFOS联盟的两个大型荟萃分析中发现的与腰椎骨密度(LS-BMD)相关的区域。不能排除GWAS发现中的假阳性关联，然而，发现和复制设置的低功率设置(适用于识别风险效应大小)可能仍然与1.10的效应大小一致，更多的是复杂性状中预期的类型。需要在标准化表型定义的研究中做出更大的努力，以确认或拒绝该基因座与脊椎骨折风险的关系。
Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set atp< 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures atp= 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14;p= 0.17), displaying high degree of heterogeneity (I2= 57%; Qhetp= 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p= 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.