Covariate-based linkage analysis: application of a propensity score as the single covariate consistently improves...

Successful identification of genetic risk loci for complex diseases has relied on the ability to minimize disease and genetic heterogeneity to increase the power to detect linkage. One means to account for disease heterogeneity is by incorporating covariate data. However, the inclusion of each covariate will add one degree of freedom to the allele sharing based linkage test, which may in fact decrease power. We explore the application of a propensity score, which is typically used in causal inference to combine multiple covariates into a single variable, as a means of allowing for multiple covariates with the addition of only one degree of freedom. In this study, binary trait data, simulated under various models involving genetic and environmental effects, were analyzed using a nonparametric linkage statistic implemented in LODPAL. Power and type I error rates were evaluated. Results suggest that the use of the propensity score to combine multiple covariates as a single covariate consistently improves the power compared to an analysis including no covariates, each covariate individually, or all covariates simultaneously. Type I error rates were inflated for analyses with covariates and increased with increasing number of covariates, but reduced to nominal rates with sample sizes of 1000 families. Therefore, we recommend using the propensity score as a single covariate in the linkage analysis of a trait suspected to be influenced by multiple covariates because of its potential to increase the power to detect linkage, while controlling for the increase in the type I error.