Gulcher J, Kong A, Stefansson K
deCODE Genetics, Inc., Reykjavik, Iceland.
Cancer J. 2001 Jan-Feb;7(1):61-8.
The goal of modern human genetics is to correlate genes with disease or, more specifically, relate genetic variation to phenotypic variation. Although this correlation is usually straightforward in the Mendelian disorders, it has proved to be much more difficult to find in the common diseases because they appear to be more complex, likely involving an interplay among multiple genes and between genes and the environment. Although the strategy of linkage mapping of families was very successful when it was applied to the rare monogenic diseases, few common diseases have been mapped to statistical significance. Many investigators are now abandoning linkage analysis altogether and are moving to a candidate gene case-control strategy. In this article, we describe a genealogic approach to mapping human disease genes and provide three examples of how we have used it to map common diseases to statistical significance. We focus on a simple population with little historic migration and use a computerized genealogy database to increase the number of patients who can be compared with other affected relatives through high-density microsatellite genotyping. The genealogy helps determine which phenotypic classification is inherited and therefore possible to map. It may represent a more efficient strategy than candidate gene case-control studies for determination of what alleles or haplotypes are shared by patients in a population. We suggest that the genetics community not give up on linkage analysis, nor should it assume that the common diseases are too complex to map.
现代人类遗传学的目标是将基因与疾病关联起来，或者更具体地说，是将基因变异与表型变异联系起来。虽然这种关联在孟德尔疾病中通常很直接，但在常见疾病中却很难找到，因为它们似乎更为复杂，可能涉及多个基因之间以及基因与环境之间的相互作用。尽管家系连锁图谱绘制策略在应用于罕见单基因疾病时非常成功，但很少有常见疾病被定位到具有统计学意义的程度。现在许多研究人员完全放弃了连锁分析，转而采用候选基因病例对照策略。在本文中，我们描述了一种绘制人类疾病基因图谱的系谱方法，并提供了三个我们如何使用该方法将常见疾病定位到具有统计学意义的例子。我们聚焦于一个历史迁移较少的简单人群，并使用计算机化的系谱数据库，通过高密度微卫星基因分型来增加可与其他患病亲属进行比较的患者数量。系谱有助于确定哪些表型分类是可遗传的，因此是可以定位的。对于确定人群中患者共享哪些等位基因或单倍型而言，它可能是一种比候选基因病例对照研究更有效的策略。我们建议遗传学领域不要放弃连锁分析，也不应认为常见疾病过于复杂而无法定位。
