JASPER: fast, powerful, multitrait association testing in structured samples gives insight on pleiotropy in gene expression

Abstract

Joint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits and microbiome abundances. It allows for covariates, ascertainment and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, some of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples.