Title | Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Chen, H, Huffman, JE, Brody, JA, Wang, C, Lee, S, Li, Z, Gogarten, SM, Sofer, T, Bielak, LF, Bis, JC, Blangero, J, Bowler, RP, Cade, BE, Cho, MH, Correa, A, Curran, JE, de Vries, PS, Glahn, DC, Guo, X, Johnson, AD, Kardia, S, Kooperberg, C, Lewis, JP, Liu, X, Mathias, RA, Mitchell, BD, O'Connell, JR, Peyser, PA, Post, WS, Reiner, AP, Rich, SS, Rotter, JI, Silverman, EK, Smith, JA, Vasan, RS, Wilson, JG, Yanek, LR, Redline, S, Smith, NL, Boerwinkle, E, Borecki, IB, L Cupples, A, Laurie, CC, Morrison, AC, Rice, KM, Lin, X |
Corporate Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group |
Journal | Am J Hum Genet |
Volume | 104 |
Issue | 2 |
Pagination | 260-274 |
Date Published | 2019 Feb 07 |
ISSN | 1537-6605 |
Keywords | Chromosomes, Human, Pair 4, Cloud Computing, Female, Fibrinogen, Genetic Association Studies, Genetics, Population, Humans, Male, Models, Genetic, National Heart, Lung, and Blood Institute (U.S.), Precision Medicine, Research Design, Time Factors, United States, Whole Genome Sequencing |
Abstract | 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. |
DOI | 10.1016/j.ajhg.2018.12.012 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 30639324 |
PubMed Central ID | PMC6372261 |
Grant List | R35 CA197449 / CA / NCI NIH HHS / United States R01 HL131136 / HL / NHLBI NIH HHS / United States U19 CA203654 / CA / NCI NIH HHS / United States R01 HL139553 / HL / NHLBI NIH HHS / United States R01 HL137922 / HL / NHLBI NIH HHS / United States R01 HL119443 / HL / NHLBI NIH HHS / United States R35 HL135818 / HL / NHLBI NIH HHS / United States U01 HL137162 / HL / NHLBI NIH HHS / United States P01 CA134294 / CA / NCI NIH HHS / United States U01 HG009088 / HG / NHGRI NIH HHS / United States P20 GM121334 / GM / NIGMS NIH HHS / United States R00 HL130593 / HL / NHLBI NIH HHS / United States U54 GM115428 / GM / NIGMS NIH HHS / United States K01 HL135405 / HL / NHLBI NIH HHS / United States U01 HL120393 / HL / NHLBI NIH HHS / United States R01 HL113338 / HL / NHLBI NIH HHS / United States |
Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.
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