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一种类基因系列罕见变异关联测试,用于候选基因发现

Zachary R McCaw¹, Colm O'Dushlaine¹, Hari Somineni¹

¹Insitro, South San Francisco, CA, USA.

American journal of human genetics

|July 26, 2023

概括

我们开发了一种新的基因测试,编码变异等位基因序列测试 (COAST),以识别具有等位基因序列的基因,这些基因序列显示了基因功能和表型严重程度之间的剂量反应关系. 与现有的方法相比,COAST显著改善了对脂质和细胞计数特征的基因特征关联的检测.

科学领域:

遗传学是一个遗传学.
统计遗传学统计遗传学
生物信息学是一种生物信息学.

背景情况:

基序列,其中增加突变严重程度与表型效应相关,在治疗上是相关的.
现有的罕见变异关联测试可能无法完全捕获来自等位基序列的信号.
识别具有等位基因序列的基因可以提供对基因功能和疾病机制的见解.

研究的目的:

开发和验证一种新的基于基因的罕见变异关联测试,即编码变异等位基因序列测试 (COAST),专门用于检测等位基因序列.
通过模拟来评估COAST在I型错误控制和统计能力方面的性能.
将COAST应用于大规模的全外因组测序数据,以识别与循环脂和细胞计数特征相关的新型基因特征关联.

主要方法:

开发COAST,集成各种协会模型,基于负载测试和SKAT.
进行了广泛的模拟,以评估COAST在不同基因架构和效果大小模式下的性能.
将COAST应用到英国生物库的全外因组测序数据 (n=145,735) 中,用于对脂质和细胞计数特征的关联分析.

主要成果:

模拟证实COAST保持了I型错误,并提高了检测具有单调效应大小模式的等位序列的功率.
与SKAT-O相比,COAST在循环脂特征上发现了29%更多的Bonferroni显著关联,在细胞计数特征上发现了82%的关联.
所有COAST识别的关联都得到了外部罕见变体 (Genebass) 或常见变体 (GWAS目录) 数据的支持,包括新发现如ANGPTL4和甘油三等.

结论:

COAST是一种强大而有效的工具,用于识别含有等位基因序列的基因,特别是当应用于罕见变异数据时.
该方法增强了与复杂的人类特征相关的基因特征关联的发现.
COAST为遗传研究提供了一种有价值的方法,通过利用等位基因序列固有的剂量反应关系来改进现有方法.

关键词:

基序列的基序列基于基因的基因测试试验.罕见变异关联测试罕见变异关联测试目标识别目标识别变体的病原性变体的病原性.整体外因子测序的测序

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