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With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.
Pubmed ID: 30639324 RIS Download
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The JHS is the largest single-site longitudinal, population-based, cohort study of 5,302 persons initiated in the fall of 2000 to prospectively investigate the determinants of CVD among African Americans in the Jackson, MS metropolitan statistical area. The JHS investigates the various genotype and phenotype factors that affect high blood pressure, heart disease, strokes, diabetes and other important diseases in African Americans. The primary objective of the Jackson Heart Study is to investigate the causes of cardiovascular disease (CVD) in African Americans to learn how to best prevent this group of diseases in the future. More specific objectives include: 1. Identification of factors, which influence the development, and worsening of CVD in African Americans, with an emphasis on manifestations related to high blood pressure (such as remodeling of the left ventricle of the heart, coronary artery disease, heart failure, stroke and disorders affecting the blood vessels of the kidney). 2. Building research capabilities in minority institutions at the undergraduate and graduate level by developing partnerships between minority and majority institutions and enhancing participation of minority investigators in large-scale epidemiologic studies. 3. Attracting minority students to and preparing them for careers in health sciences.
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