Identifying rare-variant associations in parent-child trios using a Gaussian support vector machine

As the availability of cost-effective high-throughput sequencing technology increases, genetic research is beginning to focus on identifying the contributions of rare variants (RVs) to complex traits. Using RVs to detect associated genes requires statistical approaches that mitigate the lack of power with the analysis of single RVs. Here we report the development and application of an approach that aggregates and evaluates the transmissions of RVs in parent-child trios. An initial score that incorporates the distortion in transmission of the observed RVs from the parents to their offspring is calculated for each variant. The scores are analyzed using a support vector machine that handles these data by mapping the transmission distortion of the multiple RVs into a one-dimensional score in a nonlinear fashion when parent-child trios with affected and nonaffected children are contrasted. We refer to this approach as Trio-SVM. A total of 275 trios were available in the Genetic Analysis Workshop 18 data for analysis. Because of their nonindependence and the extended linkage disequilibrium (LD) within pedigrees, Trio-SVM was vulnerable to type I errors in detecting association. Using the GAW18 data with simulated trait values, Trio-SVM has an appropriate type I error, but it lacks power with a sample of 267 trios. Larger samples of 500 to 1000 trios, derived from combining the simulated data, provided sufficient power. Two chromosome 3 candidate genes were tested in the real GAW18 data with Trio-SVM, and they showed marginal associations with hypertension.