Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
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DOI：
10.1093/hmg/ddt675
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Kaptoge, Stephen K.
中科院分区：
文献类型：
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作者：
Moayyeri, Alireza;Hsu, Yi-Hsiang;Kaptoge, Stephen K.
足跟的定量超声可捕获独立预测骨折风险的足跟骨特性，并通过x射线（DXA）评估骨矿物质密度（BMD），可能是评估骨质疏松症和骨折风险的方便替代方法。我们对全基因组关联（GWA）研究进行了荟萃分析，以评估13个发现队列中足跟宽带超声衰减（BUA, n = 14 260）、声速（VOS, n = 15 514）和骨密度（n = 4566）的遗传决定因素。独立复制包括7个具有GWA数据的队列（在计算机中n = 11 452）和15个队列的新基因分型（新生n = 24 902）。在发现和复制队列的随机效应、荟萃分析中，9个单核苷酸多态性（snp）与足跟骨特性具有全基因组显著相关性（P < 5 × 10(-8)）。除了先前发现的骨质疏松易感基因内或附近的snp，包括ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 （10q21.1: rs7902708）和GPATCH1 (19q13.11: rs10416265)，我们在染色体11q14.2上发现了一个新的位点（rs597319靠近TMEM135，一个最近与成骨细胞发生和寿命相关的基因）显著与BUA和VOS相关（P < 8.23 × 10(-14)）。在涉及多达14,985例骨折病例的25个队列的荟萃分析中，与跟骨特性相关的10个snp中有6个在P < 5 x 10（-6）时也具有与任何骨折相关的预期方向（P < 0.05），包括3个P < 0.005的snp: 6q22.33 (rs7741021), 7q31.31 （rs2908007）和10q21.1 （rs7902708）。总之，这项GWA研究揭示了中央DXA衍生的骨密度和足跟超声/DXA测量中常见的几个基因的作用，并指出了一个新的基因位点，可能有助于更好地理解骨质疏松症的病理生理。
Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.