Identifying Causal Genetic Factors

Abstract

The study of a complex disease requires careful characterization of the clinical phenotypes for study. Linkage studies, which can detect relative risks of four or greater, apply stringent diagnostic criteria and restrictive rules for family selection to assure a maximally informative collection of subjects. Clinical characterizations that are adopted for association studies must be precise and should be widely accepted to facilitate large studies. The presence of linkage disequilibrium among tightly linked loci provides a basis for genome-wide association studies. A subset of “tagging” markers that maximally characterize interindividual variability can be sought to minimize genotyping costs. Association studies can detect lower relative risks than linkage methods provided there are a limited number of causal variants at each locus and linkage disequilibrium is present (or one directly studies the causal variant). For some complex diseases there may be multiple disease variants and only moderate risks from any single locus. For these complex diseases alternative strategies using comparative genomics and animal models may be required. Admixture linkage mapping may also permit the study of larger collections of patients than is feasible using traditional linkage methods. Finally, once causal loci are identified, further genotype-phenotype studies will allow the disease to be further delineated. Such studies may also identify subsets of patients with varying responsiveness to treatments.