Extending rare-variant testing strategies: analysis of noncoding sequence and imputed genotypes.
Next Generation Sequencing Technology has revolutionized our ability to study the contribution of rare genetic variation to heritable traits. However, existing single-marker association tests are underpowered for detecting rare risk variants. A more powerful approach involves pooling methods that combine multiple rare variants from the same gene into a single test statistic. Proposed pooling methods can be limited because they generally assume high-quality genotypes derived from deep-coverage sequencing, which may not be available. In this paper, we consider an intuitive and computationally efficient pooling statistic, the cumulative minor-allele test (CMAT). We assess the performance of the CMAT and other pooling methods on datasets simulated with population genetic models to contain realistic levels of neutral variation. We consider study designs ranging from exon-only to whole-gene analyses that contain noncoding variants. For all study designs, the CMAT achieves power comparable to that of previously proposed methods. We then extend the CMAT to probabilistic genotypes and describe application to low-coverage sequencing and imputation data. We show that augmenting sequence data with imputed samples is a practical method for increasing the power of rare-variant studies. We also provide a method of controlling for confounding variables such as population stratification. Finally, we demonstrate that our method makes it possible to use external imputation templates to analyze rare variants imputed into existing GWAS datasets. As proof of principle, we performed a CMAT analysis of more than 8 million SNPs that we imputed into the GAIN psoriasis dataset by using haplotypes from the 1000 Genomes Project.
Department of Biostatistics, University of Michigan, Ann Arbor, 48109, USA.
Matthew
M
Zawistowski
Shyam
S
Gopalakrishnan
Jun
J
Ding
Yun
Y
Li
Sara
S
Grimm
Sebastian
S
Zöllner
D000483:Alleles; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D022661:RNA, Untranslated; D012306:Risk; D013223:Statistics as Topic
D022661:RNA, Untranslated