Parental phenotypes in family-based association analysis.

Family-based association designs are popular, because they offer inherent control of population stratification based on age, sex, ethnicity, and environmental exposure. However, the efficiency of these designs is hampered by current analytic strategies that consider only offspring phenotypes. Here, we describe the incorporation of parental phenotypes and, specifically, the inclusion of parental genotype-phenotype correlation terms in association tests, providing a series of tests that effectively span an efficiency-robustness spectrum. The model is based on the between-within-sibship association model presented in 1999 by Fulker and colleagues for quantitative traits and extended here to nuclear families. By use of a liability-threshold-model approach, standard dichotomous and/or qualitative disease phenotypes can be analyzed (and can include appropriate corrections for phenotypically ascertained samples), which allows for the application of this model to analysis of the commonly used affected-proband trio design. We show that the incorporation of parental phenotypes can considerably increase power, as compared with the standard transmission/disequilibrium test and equivalent quantitative tests, while providing both significant protection against stratification and a means of evaluating the contribution of stratification to positive results. This methodology enables the extraction of more information from existing family-based collections that are currently being genotyped and analyzed by use of standard approaches.