Читать книгу Genetic Analysis of Complex Disease - Группа авторов - Страница 13

Each genetically complex trait has its own peculiarities that require special attention. However, a guiding paradigm can be applied to most conditions. Originally, the general approach that was used for Mendelian single‐gene disorders was positional cloning. With the completion of the human genome reference sequence, cloning was no longer a necessary step – and therefore this general approach is better described as disease gene discovery. The classical approach (Figure 1.1) follows a generally linear series of events: defining the phenotype, identifying multi‐case families, collecting blood samples, genotyping markers, analyzing data for initial disease gene localization, refining the initial localization to define the minimum candidate region, and then sequencing genes within this region to find the causative mutation(s).

In contrast to the classical approach, the current approaches to finding genes for common and genetically complex traits are not linear, and many steps are works in progress, subject to further defining, refining, or replacement by subsequent steps. Figure 1.2 illustrates the stepwise and recursive nature of the components of a complex trait study. Each step has its own key factors that must be considered, and for complex traits, the order and emphasis of these steps on the approach will vary from study to study. This fact is underappreciated and contrasts strongly with the classical disease gene discovery approach. Indeed, many of the difficulties reconciling discordant studies of the same complex trait arise from study‐specific decisions made in the approach.

Figure 1.1 Steps in a Mendelian disease gene discovery (positional cloning) study.

Figure 1.2 Study cycle for a complex trait gene identification study.

This section discusses the steps in Figure 1.2, providing an overview of each component and a guide to the chapter(s) providing more detail on these points.