Evaluation of candidate genes in case-control studies: A statistical method to account for related subjects

Traditional case-control studies provide a powerful and efficient method fo r evaluation of association between candidate genes and disease. The sampli ng of cases from multiplex pedigrees, rather than from a catchment area, ca n increase the likelihood that genetic cases are selected. However, use of all the related cases without accounting for their biological relationship can increase the type I error rate of the statistical test. To overcome thi s problem, we present an analysis method that is used to compare genotype f requencies between cases and controls, according to a trend in proportions as the dosage of the risk allele increases. This method uses the appropriat e variance to account for the correlated family data, thus maintaining the correct type I error rate. The magnitude of the association is estimated by the odds ratio, with the variance of the odds ratio also accounting for th e correlated data. Our method makes efficient use of data collected from mu ltiplex families and should prove useful for the analysis of candidate gene s among families sampled for linkage studies. An application of our method, to family data from a prostate cancer study, is presented to illustrate th e method's utility.