Beckman Kenneth B, Abel Kenneth J, Braun Andreas, Halperin Eran
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Nucleic Acids Res. 2006;34(19):e129. doi: 10.1093/nar/gkl700. Epub 2006 Oct 4.
The genotyping of mother-father-child trios is a very useful tool in disease association studies, as trios eliminate population stratification effects and increase the accuracy of haplotype inference. Unfortunately, the use of trios for association studies may reduce power, since it requires the genotyping of three individuals where only four independent haplotypes are involved. We describe here a method for genotyping a trio using two DNA pools, thus reducing the cost of genotyping trios to that of genotyping two individuals. Furthermore, we present extensions to the method that exploit the linkage disequilibrium structure to compensate for missing data and genotyping errors. We evaluated our method on trios from CEPH pedigree 66 of the Coriell Institute. We demonstrate that the error rates in the genotype calls of the proposed protocol are comparable to those of standard genotyping techniques, although the cost is reduced considerably. The approach described is generic and it can be applied to any genotyping platform that achieves a reasonable precision of allele frequency estimates from pools of two individuals. Using this approach, future trio-based association studies may be able to increase the sample size by 50% for the same cost and thereby increase the power to detect associations.
在疾病关联研究中，对父母子三人组进行基因分型是一种非常有用的工具，因为三人组消除了群体分层效应并提高了单倍型推断的准确性。不幸的是，在关联研究中使用三人组可能会降低检验效能，因为它需要对三个个体进行基因分型，而其中只涉及四个独立的单倍型。我们在此描述一种使用两个DNA池对三人组进行基因分型的方法，从而将三人组基因分型的成本降低到对两个个体进行基因分型的成本。此外，我们还介绍了该方法的扩展，利用连锁不平衡结构来补偿缺失数据和基因分型错误。我们在科里尔研究所CEPH家系6号的三人组上评估了我们的方法。我们证明，尽管成本大幅降低，但所提出方案的基因型调用错误率与标准基因分型技术相当。所描述的方法具有通用性，可应用于任何能从两个个体的池中获得合理精确等位基因频率估计的基因分型平台。使用这种方法，未来基于三人组的关联研究可能能够以相同成本将样本量增加50%，从而提高检测关联的效能。
