Document Type

Conference Proceeding

Publication Date



Mathematics, Statistics, and Computer Science


nucleotides, genetic polymorphisms, genetic analysis, statistical hypothesis testing


The aggregation of functionally associated variants given a priori biological information can aid in the discovery of rare variants associated with complex diseases. Many methods exist that aggregate rare variants into a set and compute a single p value summarizing association between the set of rare variants and a phenotype of interest. These methods are often called gene-based, rare variant tests of association because the variants in the set are often all contained within the same gene. A reasonable extension of these approaches involves aggregating variants across an even larger set of variants (eg, all variants contained in genes within a pathway). Testing sets of variants such as pathways for association with a disease phenotype reduces multiple testing penalties, may increase power, and allows for straightforward biological interpretation. However, a significant variant-set association test does not indicate precisely which variants contained within that set are causal. Because pathways often contain many variants, it may be helpful to follow-up significant pathway tests by conducting gene-based tests on each gene in that pathway to narrow in on the region of causal variants. In this paper, we propose such a multistep approach for variant-set analysis that can also account for covariates and complex pedigree structure. We demonstrate this approach on simulated phenotypes from Genetic Analysis Workshop 19. We find generally better power for the multistep approach when compared to a more conventional, single-step approach that simply runs gene-based tests of association on each gene across the genome. Further work is necessary to evaluate the multistep approach on different data sets with different characteristics.


From Genetic Analysis Workshop 19, Vienna, Austria, August 24-26 2014.

The electronic version of this article can be found online at

Source Publication Title

BMC Proceedings


BioMed Central




Supplement 7

First Page