Wessel Jennifer, Schork Andrew J, Tiwari Hemant K, Schork Nicholas J
Center for Human Genetics and Genomics, University of California San Diego, La Jolla, CA, USA.
Genet Epidemiol. 2007 Nov;31(7):789-96. doi: 10.1002/gepi.20241.
Genetic association studies are becoming commonplace due to the availability of cost-effective yet sophisticated DNA sequencing and genotyping resources and technologies. In addition, technologies designed to identify molecular and subclinical phenotypes that reflect disease pathogenesis are continually being developed and refined (consider, e.g., imaging technologies, microarray-based gene expression and proteomic platforms, histological analyses of excised tissues, etc.). Unfortunately, the large-scale use of many of these molecular and subclinical phenotyping technologies in genetic association studies is difficult logistically and is currently cost-prohibitive. In this paper, we consider efficient designs for testing the association between particular genetic variations and expensive, yet appropriate, subclinical phenotypes of relevance to a disease that take advantage of twins or sibling pairs discordant for genotypes at the locus (or loci) being tested. We demonstrate that including genotypically discordant twins or siblings in an association study can result in a substantial increase in power over designs that use monozygotic twins or only unrelated individuals. We ultimately argue that, from a practical standpoint, sampling from existing family or twin-based cohorts in which: (1) follow-up studies of a genetic association are warranted in order to assess the in vivo significance of an association with respect to more refined pathological phenotypes; and/or (2) large-scale, genome-wide linkage and association studies have been pursued that have focused on clinical endpoints for which the study subjects have consented to more elaborate follow-up studies, is a powerful way to test associations.
由于具备经济高效且先进的DNA测序和基因分型资源及技术，基因关联研究正变得越来越普遍。此外，旨在识别反映疾病发病机制的分子和亚临床表型的技术也在不断发展和完善（例如，可考虑成像技术、基于微阵列的基因表达和蛋白质组学平台、切除组织的组织学分析等）。不幸的是，在基因关联研究中大规模使用许多此类分子和亚临床表型分析技术在后勤方面存在困难，且目前成本过高。在本文中，我们考虑了一些高效设计，用于检验特定基因变异与与某疾病相关的昂贵但合适的亚临床表型之间的关联，这些设计利用了在所测试的一个或多个基因座上基因型不一致的双胞胎或同胞对。我们证明，在关联研究中纳入基因型不一致的双胞胎或同胞，相比于使用同卵双胞胎或仅使用无关个体的设计，能够显著提高检验效能。我们最终认为，从实际角度来看，从现有的基于家庭或双胞胎的队列中进行抽样是一种强大的关联检验方法，这些队列满足以下条件：（1）有必要对基因关联进行后续研究，以评估与更精细病理表型的关联在体内的意义；和/或（2）已经开展了大规模的全基因组连锁和关联研究，这些研究聚焦于临床终点，且研究对象已同意进行更详细的后续研究。
