A Generalized Family-Based Association Test for Dichotomous Traits
A Generalized Family-Based Association Test for Dichotomous Traits
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DOI：
10.1016/j.ajhg.2009.08.003
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发表时间：
2009-09-11
影响因子：
9.8
通讯作者：
Rich, Stephen S.
中科院分区：
文献类型：
--
作者：
Chen, Wei-Min;Manichaikul, Ani;Rich, Stephen S.
基因分型技术的最新进展使得利用大规模关联分析进行疾病基因图谱分析成为可能。强大而稳健的基于家族的关联方法对于成功的基因定位至关重要。我们提出了一种基于家族的关联方法，即广义不平衡检验（GDT），其中利用所有不一致的相对对的基因型差异来评估家族内的关联。 GDT 相对于现有方法的改进有三方面：(1) 有效整合了一级亲属以外的信息，与现有测试相比，功效显着提高； (2) GDT 统计是通过稳健的技术实现的，该技术不依赖于大样本理论，从而导致进一步的功率增益，尤其是在高显着性水平下； (3) 纳入基于家庭规模的协变量和权重。广泛的计算机模拟以及对 1 型糖尿病遗传学联盟 (T1DGC) 最近发布的大规模全基因组连锁数据的应用证明了 GDT 相对于现有方法的优势。在我们的模拟中，GDT 始终优于针对常见疾病的其他测试，并且经常优于针对罕见疾病的其他测试；在 8 个扩展谱系场景中，有 6 个场景的性能提升 > 13%。其他研究报告了 GDT 确定的所有六种最强关联，而现有方法只能确定其中三到四种关联。对于基因 UBASH3A 的 T1D 关联，GDT 产生全基因组显着性 (p = 4.3 x 10(-6))，比已发表的显着性 (p = 10(-4)) 强得多。
Recent advances in genotyping technology make it possible to utilize large-scale association analysis for disease-gene mapping. Powerful and robust family-based association methods are crucial for successful gene mapping. We propose a family-based association method, the generalized disequilibrium test (GDT), in which the genotype differences of all discordant relative pairs are utilized in assessing association within a family. The improvement of the GDT over existing methods is threefold: (1) information beyond first-degree relatives is incorporated efficiently, yielding substantial gains in power in comparison to existing tests; (2) the GDT statistic is implemented via a robust technique that does not rely on large sample theory resulting in further power gains, especially at high levels of significance; and (3) covariates and weights based on family size are incorporated. Advantages of the GDT over existing methods are demonstrated by extensive computer simulations and by application to recently published large-scale genome-wide linkage data from the Type 1 Diabetes Genetics Consortium (T1DGC). In our simulations, the GDT consistently outperforms other tests for a common disease and frequently outperforms other tests for a rare disease; the power improvement is > 13% in 6 out of 8 extended pedigree scenarios. All of the six strongest associations identified by the GDT have been reported by other studies, whereas only three or four of these associations can be identified by existing methods. For the T1D association at gene UBASH3A, the GDT resulted in a genome-wide significance (p = 4.3 x 10(-6)), much stronger than the published significance (p = 10(-4)).