考希组合方法用于检测与定量表型相关的罕见变异的基因环境相互作用
1State Key Laboratory of Integrated Services Networks, Xidian University, 2 South Taibai Road, Xi'an, Shaanxi, 710071, China. jinxiaoqin@stu.xidian.edu.cn.
Heredity
|July 22, 2023
概括
新的基因环境相互作用 (GEI) 测试提高了检测复杂疾病中罕见变异效应的能力. 综合考奇组合GEI测试 (CCGEI-O) 在模拟和现实数据分析中显著优于现有方法.
科学领域:
- 遗传学和基因组学 遗传学和基因组学
- 统计遗传学 统计遗传学
- 复杂疾病研究 复杂疾病研究
背景情况:
- 基因与环境的相互作用对于理解复杂的疾病机制至关重要.
- 现有的GEI测试缺乏检测罕见变异的能力,特别是当只有少数具有因果关系时.
- 聚合的考契关联测试 (ACAT) 是一个强大的工具,用于结合关联测试的p值.
研究的目的:
- 为罕见变种开发具有增强功率的新型GEI测试.
- 通过模拟来评估拟议测试与现有方法的性能.
- 将新的GEI测试应用于真实世界基因组范围的基因与BMI相互作用的关联数据.
主要方法:
- 扩展聚合考奇关联测试 (ACAT) 以开发三个新的GEI测试:CCGEI-F,CCGEI-R和CCGEI-O.
- CCGEI-F和CCGEI-R使用ACAT结合了单个变异的GEI p值.
- CCGEI-O结合了多个GEI测试中的p值.
- 进行了数值模拟,以与现有测试 (INT-FIX,INT-RAN,TOW-GE) 进行功率比较.
- 用英国生物银行的全外体序列测序数据进行了全基因组综合分析,以检测基因-BMI相互作用.
主要成果:
- 对于少数因果变异,CCGEI-F,CCGEI-R和CCGEI-O显示出大约比INT-FIX和INT-RAN高5%的功率.
- 与竞争测试相比,CCGEI-O在所有模拟条件下始终提供了明显更高的功率.
- 全基因组分析确定了KCNC4,GAR1,FAM120AOS和NT5C3B的潜在基因-BMI相互作用,具有暗示意义水平 (1.0 × 10-4).
结论:
- 拟议的Cauchy组合GEI测试,特别是CCGEI-O,为检测涉及罕见变异的GEI提供了更好的能力.
- 这些新方法提高了发现由基因与环境相互作用影响的复杂疾病机制的能力.
- 确定的基因-BMI相互作用需要进一步研究它们在血压调节中的作用.
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