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Abstract Genome-wide Association Studies (GWAS) methods have identified individual single-nucleotide polymorphisms (SNPs) significantly associated with specific phenotypes. Nonetheless, many complex diseases are polygenic and are controlled by multiple genetic variants that are usually non-linearly dependent. These genetic variants are marginally less effective and remain undetected in GWAS analysis. Kernel-based tests (KBT), which evaluate the joint effect of a group of genetic variants, are therefore critical for complex disease analysis. However, choosing different kernel functions in KBT can significantly influence the type I error control and power, and selecting the optimal kernel remains a statistically challenging task. A few existing methods suffer from inflated type 1 errors, limited scalability, inferior power or issues of ambiguous conclusions. Here, we present a new Bayesian framework, BayesKAT (https://github.com/wangjr03/BayesKAT), which overcomes these kernel specification issues by selecting the optimal composite kernel adaptively from the data while testing genetic associations simultaneously. Furthermore, BayesKAT implements a scalable computational strategy to boost its applicability, especially for high-dimensional cases where other methods become less effective. Based on a series of performance comparisons using both simulated and real large-scale genetics data, BayesKAT outperforms the available methods in detecting complex group-level associations and controlling type I errors simultaneously. Applied on a variety of groups of functionally related genetic variants based on biological pathways, co-expression gene modules and protein complexes, BayesKAT deciphers the complex genetic basis and provides mechanistic insights into human diseases.
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A novel application of data‐consistent inversion to overcome spurious inference in genome‐wide association studies
Abstract The genome‐wide association studies (GWAS) typically use linear or logistic regression models to identify associations between phenotypes (traits) and genotypes (genetic variants) of interest. However, the use of regression with the additive assumption has potential limitations. First, the normality assumption of residuals is the one that is rarely seen in practice, and deviation from normality increases the Type‐I error rate. Second, building a model based on such an assumption ignores genetic structures, like, dominant, recessive, and protective‐risk cases. Ignoring genetic variants may result in spurious conclusions about the associations between a variant and a trait. We propose an assumption‐free model built upon data‐consistent inversion (DCI), which is a recently developed measure‐theoretic framework utilized for uncertainty quantification. This proposed DCI‐derived model builds a nonparametric distribution on model inputs that propagates to the distribution of observed data without the required normality assumption of residuals in the regression model. This characteristic enables the proposed DCI‐derived model to cover all genetic variants without emphasizing on additivity of the classic‐GWAS model. Simulations and a replication GWAS with data from the COPDGene demonstrate the ability of this model to control the Type‐I error rate at least as well as the classic‐GWAS (additive linear model) approach while having similar or greater power to discover variants in different genetic modes of transmission.
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- Award ID(s):
- 2208460
- PAR ID:
- 10534198
- Publisher / Repository:
- Genetic Epidemiology
- Date Published:
- Journal Name:
- Genetic Epidemiology
- ISSN:
- 0741-0395
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1002/gepi.22563
