Increasing the power of association studies with affected families, unrelated cases and controls.
Increasing the power of association studies with affected families, unrelated cases and controls.
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DOI：
10.3389/fgene.2013.00200
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发表时间：
2013
影响因子：
3.7
通讯作者：
Cerise J
中科院分区：
文献类型：
--
作者：
Stewart WC;Cerise J
在研究遗传疾病的遗传学时，研究人员经常收集受影响家庭、不相关病例和健康对照的数据。然而，这种异构数据的联合分析是困难的，而同质子集的简单分析往往是次优的。例如，虽然关联的病例对照试验对等位基因频率差异很敏感，但从杂合亲本到其受影响后代的风险等位基因优先传递通常被忽略。同样，遗传不平衡检验（TDT）在检测关联时也不能考虑等位基因频率的差异。为了增强现代基因研究的力量，我们提出了POPFAM——一种快速有效的关联测试，可以容纳大量受影响的家庭，不相关的病例和对照。我们使用模拟来评估POPFAM在不同遗传模型和次要等位基因频率下的I型误差和功率。为了比较，我们检验了竞争方法的力量：趋势检验，Wald检验（相当于TDT）和SCOUT。我们的结果表明，POPFAM保持了正确的I型误差，并且比趋势检验或TDT更强大。它的表现与SCOUT一样好，甚至比SCOUT更好，SCOUT是专门为病例-父母/病例-对照数据开发的。此外，当应用于401个1型糖尿病家族的人白细胞抗原基因型时，POPFAM证实了先前报道的DRB1*03:01与微血管并发症之间的相关性（p = 0.04）。总的来说，我们希望我们提出的测试能够促进临床重要基因组区域的识别，并更好地为后续测序工作的设计提供信息。
When studying the genetics of inherited diseases, researchers often collect data on affected families, unrelated cases, and healthy controls. However, the joint analysis of such heterogeneous data is difficult, and the simpler analysis of homogeneous subsets is often suboptimal. For example, while case-control tests of association are sensitive to allele frequency differences, the preferential transmission of risk alleles from heterozygous parents to their affected offspring is typically ignored. Similarly, the transmission disequilibrium test (TDT) fails to incorporate the difference in allele frequencies when testing for association. To boost the power of modern genetic studies, we propose POPFAM – a fast and efficient test of association that can accommodate large affected families, unrelated cases, and controls. We use simulations to assess the type I error and power of POPFAM across different genetic models, and minor allele frequencies. For comparison, we examine the power of competing methods: the trend test, a Wald test (equivalent to the TDT), and SCOUT. Our results show that POPFAM maintains the correct type I error, and that it is more powerful than the trend test or the TDT. It performs as well as, or better than the likelihood ratio test SCOUT, which was developed specifically for case-parent/case-control data. Furthermore, when applied to the human leukocyte antigen genotypes of 401 type 1 diabetic families, POPFAM confirmed the previously reported association between DRB1*03:01 and microvascular complications (p = 0.04). In general, we expect our proposed test to facilitate the identification of clinically important genomic regions, and to better inform the design of follow-up sequencing efforts.