Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, Massachusetts, USA.
PLoS Genet. 2010 Jun 10;6(6):e1000977. doi: 10.1371/journal.pgen.1000977.
Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.
骨质疏松症是一种复杂的疾病，常导致老年人骨折。全基因组关联研究（GWAS）已成为一种无偏的方法，用于识别可能影响健康的基因组变异。然而，迄今为止发现的遗传变异仅解释了复杂性状遗传力的一小部分。由于遗传效应大小适中且功效不足，真正的关联信号可能无法基于严格的全基因组显著性阈值来揭示。在这里，我们利用 SNP 和转录数组，并整合与骨骼系统相关的 GWAS 和表达特征分析在细胞和动物模型中，优先发现骨质疏松相关性状的新候选基因，包括腰椎（LS）和股骨颈（FN）的骨矿物质密度（BMD），以及髋部的几何指数（股骨颈干角，NSA；股骨颈长度，NL；和窄颈宽度，NW）。对来自 7633 名白种女性和 3657 名男性的 GWAS 的两阶段荟萃分析显示，三个新的位点与骨质疏松相关性状相关，包括 1p13.2 染色体（RAP1A，p = 3.6x10(-8)）、2q11.2（TBC1D8）和 18q11.2（OSBPL1A），并证实了 TNFRSF11B/OPG 基因附近的一个先前报道的区域。我们还根据它们在骨骼代谢中的潜在参与，优先考虑了 16 个提示全基因组显著的候选基因。其中，3 个候选基因与女性的 BMD 相关。值得注意的是，这 3 个基因中的 2 个（GPR177，p = 2.6x10(-13)；SOX6，p = 6.4x10(-10)）与女性的 BMD 相关，已在 BMD 的大规模荟萃分析中成功复制，但没有一个非优先的候选基因（与 BMD 相关）做到了。我们的结果支持我们的优先策略的概念。在没有确定基因的直接生物学支持的情况下，我们强调了使用细胞或全动物模型中与骨骼系统相关的公共表达谱进行后续功能特征描述的效率，以优先考虑候选基因进行进一步的功能验证。
