Family-based designs in the age of large-scale gene-association studies

Key Points Either population-based or family-based designs can be used in gene-association studies. Population-based designs use unrelated individuals; family-based designs use probands and their relatives, typically either parents or siblings. Genetic-association studies face the obstacles of population substructures and multiple testing. Family-based designs are favoured because they are robust against confounding due to population substructures and test both linkage and association. Case–control designs are preferred for the relative ease of data collection. They have modest power advantages, depending on the prevalence of the disease. Family-based designs can be extended to incorporate pedigrees and complex phenotypes. Screening tools are available for family-based designs that allow the multiple-testing problem, which is an important issue in whole-genome association studies, to be handled. Although they are sometimes overlooked, family-based designs provide important advantages for detecting genetic associations in studies of complex disease. In particular, they provide a means of overcoming the problems that arise when multiple hypotheses are tested in genome-wide association studies. Both population-based and family-based designs are commonly used in genetic association studies to locate genes that underlie complex diseases. The simplest version of the family-based design — the transmission disequilibrium test — is well known, but the numerous extensions that broaden its scope and power are less widely appreciated. Family-based designs have unique advantages over population-based designs, as they are robust against population admixture and stratification, allow both linkage and association to be tested for and offer a solution to the problem of model building. Furthermore, the fact that family-based designs contain both within- and between-family information has substantial benefits in terms of multiple-hypothesis testing, especially in the context of whole-genome association studies.