Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
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DOI：
10.1371/journal.pgen.1003247
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Ohlsson C
中科院分区：
文献类型：
--
作者：
Paternoster L;Lorentzon M;Lehtimäki T;Eriksson J;Kähönen M;Raitakari O;Laaksonen M;Sievänen H;Viikari J;Lyytikäinen LP;Mellström D;Karlsson M;Ljunggren O;Grundberg E;Kemp JP;Sayers A;Nethander M;Evans DM;Vandenput L;Tobias JH;Ohlsson C
在骨质疏松症领域，大多数先前的遗传流行病学研究都集中在复杂性状面骨矿物质密度（aBMD）的遗传学上，无法区分皮质体积骨密度（vBMD）、小梁骨密度和骨微结构性状的遗传决定因素。本研究的目的是通过外周定量计算机断层扫描（pQCT）分析，分别确定这些骨骼特征的遗传决定因素。分别对皮质和小梁vBMDs进行GWA meta分析。皮质vBMD GWA meta分析（n = 5,878）和复制（n = 1,052）鉴定出四个独立的基因座具有全基因组意义（RANKL, rs1021188, p = 3.6×10−14;LOC285735, rs271170, p = 2.7×10−12；OPG, rs7839059, p = 1.2×10−10;ESR1/C6orf97, rs6909279, p = 1.1×10−9）。小梁vBMD GWA荟萃分析（n = 2,500）和复制（n = 1,022）确定了一个具有全基因组显著性的位点（FMN2/GREM2, rs9287237, p = 1.9×10−9）。高分辨率pQCT分析提供了骨骼微观结构的信息，在GOOD队列的一个子集（n = 729）中可用。Rs1021188与皮质孔隙度显著相关，rs9287237与骨小梁分数显著相关。在MrOS瑞典队列中，FMN2/GREM2位点的遗传变异与骨折风险（每额外T等位基因的风险比为0.75,95%置信区间为0.60-0.93）和人成骨细胞中GREM2的表达相关。总之，鉴定出了5个与小梁或皮质vBMD相关的基因位点。其中两个（FMN2/GREM2和LOC285735）是新的骨相关基因座，而其他三个先前已报道与aBMD相关。与骨皮质和骨小梁参数相关的遗传变异不同，强调了骨参数遗传学的复杂性。我们提出RANKL基因座的遗传变异至少部分地通过对皮质孔隙度的影响影响皮质vBMD， FMN2/GREM2基因座的遗传变异影响成骨细胞中GREM2的表达，从而影响骨小梁的数量和厚度以及骨折风险。骨质疏松症是一种常见的高度遗传性骨骼疾病，其特征是骨矿物质密度（BMD）降低和骨微观结构恶化，导致骨折风险增加。以前的遗传流行病学研究大多集中在复杂性状骨密度的遗传学上，无法分离骨小梁和骨皮质间室以及骨微观结构的遗传决定因素。小梁和皮质bmd可以分别通过计算机断层扫描进行分析。因此，我们对骨小梁和骨小梁的骨密度进行了单独的全基因组关联研究，证明了骨小梁和骨小梁骨密度的遗传决定因素是不同的。RANKL、LOC285735、OPG和ESR1位点的遗传变异与皮质骨密度有关，而FMN2/GREM2位点的遗传变异与小梁骨密度有关。其中两个是新的骨骼相关位点。骨骼微观结构的后续分析表明，RANKL基因座的遗传变异与皮质孔隙度有关，FMN2/GREM2基因座与小梁数量和厚度有关。我们提出RANKL基因座的遗传变异通过对皮质孔隙度的影响影响皮质骨密度，FMN2/GREM2基因座的遗传变异通过对小梁数量和厚度的影响影响小梁骨密度和骨折风险。
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk. Osteoporosis is a common highly heritable skeletal disease characterized by reduced bone mineral density (BMD) and deteriorated bone microstructure, resulting in an increased risk of fracture. Most previous genetic epidemiology studies have focused on the genetics of the complex trait BMD, not being able to separate genetic determinants of the trabecular and cortical bone compartments and bone microstructure. The trabecular and cortical BMDs can be analysed separately by computed tomography. Therefore, we performed separate genome-wide association studies for trabecular and cortical BMDs, demonstrating that the genetic determinants of cortical and trabecular BMDs differ. Genetic variants in the RANKL, LOC285735, OPG, and ESR1 loci were associated with cortical BMD, while a genetic variant in the FMN2/GREM2 locus was associated with trabecular BMD. Two of these are novel bone-related loci. Follow-up analyses of bone microstructure demonstrated that a genetic variant in the RANKL locus is associated with cortical porosity and that the FMN2/GREM2 locus is associated with trabecular number and thickness. We propose that a genetic variant in the RANKL locus influences cortical BMD via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences trabecular BMD and fracture risk via effects on both trabecular number and thickness.
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