Sequence Kernel Association Tests for the Combined Effect of Rare and Common Variants

Abstract

Recent developments in sequencing technologies have made it possible to uncover both rare and common genetic variants. Genome-wide association studies (GWASs) can test for the effect of common variants, whereas sequence-based association studies can evaluate the cumulative effect of both rare and common variants on disease risk. Many groupwise association tests, including burden tests and variance-component tests, have been proposed for this purpose. Although such tests do not exclude common variants from their evaluation, they focus mostly on testing the effect of rare variants by upweighting rare-variant effects and downweighting common-variant effects and can therefore lose substantial power when both rare and common genetic variants in a region influence trait susceptibility. There is increasing evidence that the allelic spectrum of risk variants at a given locus might include novel, rare, low-frequency, and common genetic variants. Here, we introduce several sequence kernel association tests to evaluate the cumulative effect of rare and common variants. The proposed tests are computationally efficient and are applicable to both binary and continuous traits. Furthermore, they can readily combine GWAS and whole-exome-sequencing data on the same individuals, when available, and are also applicable to deep-resequencing data of GWAS loci. We evaluate these tests on data simulated under comprehensive scenarios and show that compared with the most commonly used tests, including the burden and variance-component tests, they can achieve substantial increases in power. We next show applications to sequencing studies for Crohn disease and autism spectrum disorders. The proposed tests have been incorporated into the software package SKAT.

Rare Variants in the Complement Factor H–Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy

“…First, SKAT can evaluate not only the effect of rare variants but also, the cumulative effect of rare and common variants. 25 Second, SKAT allows for rare variants to have opposite effects (both effective and deleterious) on the traits. 26 Because we identified both rare and common variants as well as their gain-of-function or loss-offunction properties, we tested the genetic associations between IgAN and rare plus common variants, rare variants alone, and common variants alone in CFHR5 by SKAT.…”

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

“…[31][32][33] Such tests are necessary because standard single-marker methods used to test common variants (as in genome-wide association studies) are usually underpowered for rare variants. We selected sequence kernel association tests because they are flexible and computationally efficient and can easily be applied to genome-wide or exome-wide data.…”

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

“…We used SKAT [8] to evaluate the global contribution of sets of variants. The analysis was performed for rare (MAF<0.01), common, and all variants combined.…”