Chapman N H, Wijsman E M
Department of Biostatistics, Department of Medicine, University of Washington, Seattle, USA.
Am J Hum Genet. 1998 Dec;63(6):1872-85. doi: 10.1086/302139.
Linkage disequilibrium (LD) testing has become a popular and effective method of fine-scale disease-gene localization. It has been proposed that LD testing could also be used for genome screening, particularly as dense maps of diallelic markers become available and automation allows inexpensive genotyping of diallelic markers. We compare diallelic markers and multiallelic markers in terms of sample sizes required for detection of LD, by use of a single marker locus in a case-control study, for rare monophyletic diseases with Mendelian inheritance. We extrapolate from our results to discuss the feasibility of single-marker LD screening in more-complex situations. We have used a deterministic population genetic model to calculate the expected power to detect LD as a function of marker density, age of mutation, number of marker alleles, mode of inheritance of a rare disease, and sample size. Our calculations show that multiallelic markers always have more power to detect LD than do diallelic markers (under otherwise equivalent conditions) and that the ratio of the number of diallelic to the number of multiallelic markers needed for equivalent power increases with mutation age and complexity of mode of inheritance. Power equivalent to that achieved by a multiallelic screen can theoretically be achieved by use of a more dense diallelic screen, but mapping panels of the necessary resolution are not currently available and may be difficult to achieve. Genome screening that uses single-marker LD testing may therefore be feasible only for young (<20 generations), rare, monophyletic Mendelian diseases, such as may be found in rapidly growing genetic isolates.
连锁不平衡（LD）检测已成为精细定位疾病基因的一种常用且有效的方法。有人提出，LD检测也可用于基因组筛查，特别是当双等位基因标记的密集图谱可用，且自动化技术使得双等位基因标记的低成本基因分型成为可能时。在一项病例对照研究中，针对具有孟德尔遗传的罕见单源疾病，我们通过使用单个标记位点，比较了检测LD所需样本量方面的双等位基因标记和多等位基因标记。我们根据研究结果进行推断，以讨论在更复杂情况下单标记LD筛查的可行性。我们使用了一个确定性群体遗传模型，来计算作为标记密度、突变年龄、标记等位基因数量、罕见疾病遗传模式和样本量函数的检测LD的预期效能。我们的计算表明，在其他条件相同的情况下，多等位基因标记检测LD的效能总是高于双等位基因标记，并且获得同等效能所需的双等位基因标记数量与多等位基因标记数量之比会随着突变年龄和遗传模式复杂性的增加而升高。理论上，通过使用更密集的双等位基因筛查可以实现与多等位基因筛查相当的效能，但目前尚无所需分辨率的定位面板，且可能难以实现。因此，使用单标记LD检测的基因组筛查可能仅对年轻（<20代）、罕见、单源的孟德尔疾病可行，比如在快速增长的遗传隔离群体中可能发现的疾病。
