Candidate-gene association analysis for a continuous phenotype with a spike at zero using parent-offspring trios

In this paper, we propose the class of generalized additive models for location, scale and shape in a test for the association of genetic markers with non-normally distributed phenotypes comprising a spike at zero. The resulting statistical test is a generalization of the quantitative transmission disequilibrium test with mating type indicator, which was originally designed for normally distributed quantitative traits and parent-offspring data. As a motivational example, we consider coronary artery calcification (CAC), which can accurately be identified by electron beam tomography. In the investigated regions, individuals will have a continuous measure of the extent of calcium found or they will be calcium-free. Hence, the resulting distribution is a mixed discrete-continuous distribution with spike at zero. We carry out parent-offspring simulations motivated by such CAC measurement values in a screening population to study statistical properties of the proposed test for genetic association. Furthermore, we apply the approach to data of the Genetic Analysis Workshop 16 that are based on real genotype and family data of the Framingham Heart Study, and test the association of selected genetic markers with simulated coronary artery calcification.