Incorporation of covariates into multipoint linkage disequilibrium mapping in case-control studies

Case-control designs are commonly adopted in genetic epidemiological studies because they are cost effective and offer powerful tests for genetic and environmental risk factors, as well as their interactions. Previously, we proposed an association mapping approach to estimate the position of an unobserved disease locus as well as measuring its genetic effect on risk. The method provides a confidence interval for the estimated map position to help narrow the chromosomal region potentially harboring a disease locus. However, concerns often rise about case-control designs including possible false positives or bias due to confounders, heterogeneity or interactions among genes and between genes and environments. In the present work, we extended the multipoint linkage disequilibrium mapping approach for case-control studies to incorporate information about factors influencing the effect of causal genes to improve precision and efficiency of the estimated location. The efficiency, bias and coverage probability of this extended approach for locating a disease locus using case-control data with and without additional information on a covariate were compared through simulation. An example of a case-control study for type 2 diabetes was used to illustrate this extended method. In this study, a strong association between diabetes and a candidate gene, SCL2A10, was detected among nonobese subjects, whereas no evidence of association was found for either obese subjects or the whole sample when obesity was ignored. Simulation studies and these diabetes data both demonstrate how the efficiency of the estimated location of a disease gene can be improved substantially by incorporating information on covariates.