全基因组测序确定EN1为骨密度和骨折的决定因素
Hou-Feng Zheng1,2, Vincenzo Forgetta1,2, Yi-Hsiang Hsu3,4,5
1Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.
Nature
|September 15, 2015
概括
低频基因变异显著影响骨矿物质密度和骨折风险. 这些通过全基因组测序识别的非编码变异突显了研究复杂特征的罕见遗传变异的重要性.
科学领域:
- 遗传学和基因组学
- 骨生物学
- 骨质疏松症研究
背景情况:
- 复杂的特征和疾病受到遗传变异的影响,但低频率 (1-5%的MAF) 和罕见的 (≤1%的MAF) 变异的贡献在很大程度上是未知的.
- 骨矿物质密度 (BMD) 是高度遗传的,也是骨质疏松性骨折的关键预测因子,与常见和罕见的编码变异有关.
- 了解骨损伤和骨折风险的遗传结构对于制定有效的预防和治疗策略至关重要.
研究的目的:
- 在一般欧洲祖先群体中识别具有对骨和骨折风险显著影响的新型非编码基因变异.
- 研究低频率和罕见变异在复杂特征的遗传基础中的作用.
- 为在遗传学研究中利用全基因组测序和先进的归因方法提供理由.
主要方法:
- 使用全基因组测序 (UK10K),全外基因组测序,使用综合基因组进行深度归因,以及新的复制基因型.
- 在欧洲血统的个体中分析了大队列与BMD (n=53,236) 和骨折 (n=508,253) 的关联.
- 使用小鼠模型 (En1 ((cre/flox)) 来研究已识别的遗传变异的功能后果.
主要成果:
- 在EN1基因附近发现了一种低频率的非编码变体 (rs11692564(T),MAF=1.6%) 与之前报告的常见变体相比,对腰椎骨质量有四倍的影响.
- 这种EN1变异与骨折风险降低有关 (OR=0. 85).
- 在WNT16附近发现了另一种低频非编码变体 (rs148771817(T),MAF=1.2%) 对骨质量有显著影响 (影响大小=+0.41秒). ) 的情况.
- 从有害的编码和保存的非编码变体中观察到过多的关联信号,表明它们的重要性.
结论:
- 低频非编码变体可能对骨和骨折风险产生很大的影响.
- 这些发现强调了全基因组测序和改进的归算参考面板的价值,用于剖析复杂特征的遗传基础.
- 这项研究有助于更深入地了解骨健康和骨质疏松症的遗传结构.
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