Shifting paradigms in gene-mapping methodology for complex traits.

The analysis of genetic linkage has been highly successful in the mapping of the genes responsible for Mendelian diseases. In the past decade, attempts have been made to extend this approach to multifactorial disorders and other health-related traits. It has proved difficult, however, to obtain strong and replicable linkage findings for the common forms of heritable diseases. This, together with the rapid pace of development of molecular technology and expansion of genome sequence information, has resulted in significant shifts in research paradigm. There is an increasing recognition of the need to understand the population genetics and biometrical properties of clinically relevant traits so that phenotypes can be defined in such a way that maximises the chances of successful gene mapping. There is a trend towards systematic association analysis with increasing sophistication in the analysis of pooled DNA samples and multi-locus haplotypes, and in the use of unlinked background markers to protect against spurious associations. We can expect increasing integration between genetics, epidemiology and clinical trials leading to genetically informative designs that will not only identify susceptibility genes but also clarify how the environment influences their effects and how they may modify the response to therapeutic interventions.