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A Bayesian hierarchical variable selection prior for pathway-based GWAS using summary statistics.

ABSTRACT: While genome-wide association studies (GWASs) have been widely used to uncover associations between diseases and genetic variants, standard SNP-level GWASs often lack the power to identify SNPs that individually have a moderate effect size but jointly contribute to the disease. To overcome this problem, pathway-based GWASs methods have been developed as an alternative strategy that complements SNP-level approaches. We propose a Bayesian method that uses the generalized fused hierarchical structured variable selection prior to identify pathways associated with the disease using SNP-level summary statistics. Our prior has the flexibility to take in pathway structural information so that it can model the gene-level correlation based on prior biological knowledge, an important feature that makes it appealing compared to existing pathway-based methods. Using simulations, we show that our method outperforms competing methods in various scenarios, particularly when we have pathway structural information that involves complex gene-gene interactions. We apply our method to the Wellcome Trust Case Control Consortium Crohn's disease GWAS data, demonstrating its practical application to real data.

SUBMITTER: Yang Y

PROVIDER: S-EPMC7690328 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A Bayesian hierarchical variable selection prior for pathway-based GWAS using summary statistics.

Yang Yi Y Basu Saonli S Zhang Lin L

Statistics in medicine 20191127 6

While genome-wide association studies (GWASs) have been widely used to uncover associations between diseases and genetic variants, standard SNP-level GWASs often lack the power to identify SNPs that individually have a moderate effect size but jointly contribute to the disease. To overcome this problem, pathway-based GWASs methods have been developed as an alternative strategy that complements SNP-level approaches. We propose a Bayesian method that uses the generalized fused hierarchical structu ...[more]

PMID: 31777110

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Project description:BACKGROUND:Genome-wide association studies (GWAS) have been successful in identifying disease-associated genetic variants. Recently, an increasing number of GWAS summary statistics have been made available to the research community, providing extensive repositories for studies of human complex diseases. In particular, cross-trait associations at the genetic level can be beneficial from large-scale GWAS summary statistics by using genetic variants that are associated with multiple traits. However, direct assessment of cross-trait associations using susceptibility loci has been challenging due to the complex genetic architectures in most diseases, calling for advantageous methods that could integrate functional interpretation and imply biological mechanisms. RESULTS:We developed an analytical framework for systematic integration of cross-trait associations. It incorporates two different approaches to detect enriched pathways and requires only summary statistics. We demonstrated the framework using 25 traits belonging to four phenotype groups. Our results revealed an average of 54 significantly associated pathways (ranged between 18 and 175) per trait. We further proved that pathway-based analysis provided increased power to estimate cross-trait associations compared to gene-level analysis. Based on Fisher's Exact Test (FET), we identified a total of 24 (53) pairs of trait-trait association at adjusted pFET?<?1?×?10-?3 (pFET?<?0.01) among the 25 traits. Our trait-trait association network revealed not only many relationships among the traits within the same group but also novel relationships among traits from different groups, which warrants further investigation in future. CONCLUSIONS:Our study revealed that risk variants for 25 different traits aggregated in particular biological pathways and that these pathways were frequently shared among traits. Our results confirmed known mechanisms and also suggested several novel insights into the etiology of multi-traits.

Project description:Genome-wide association studies (GWAS) for complex diseases have focused primarily on single-trait analyses for disease status and disease-related quantitative traits. For example, GWAS on risk factors for coronary artery disease analyze genetic associations of plasma lipids such as total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides (TGs) separately. However, traits are often correlated and a joint analysis may yield increased statistical power for association over multiple univariate analyses. Recently several multivariate methods have been proposed that require individual-level data. Here, we develop metaUSAT (where USAT is unified score-based association test), a novel unified association test of a single genetic variant with multiple traits that uses only summary statistics from existing GWAS. Although the existing methods either perform well when most correlated traits are affected by the genetic variant in the same direction or are powerful when only a few of the correlated traits are associated, metaUSAT is designed to be robust to the association structure of correlated traits. metaUSAT does not require individual-level data and can test genetic associations of categorical and/or continuous traits. One can also use metaUSAT to analyze a single trait over multiple studies, appropriately accounting for overlapping samples, if any. metaUSAT provides an approximate asymptotic P-value for association and is computationally efficient for implementation at a genome-wide level. Simulation experiments show that metaUSAT maintains proper type-I error at low error levels. It has similar and sometimes greater power to detect association across a wide array of scenarios compared to existing methods, which are usually powerful for some specific association scenarios only. When applied to plasma lipids summary data from the METSIM and the T2D-GENES studies, metaUSAT detected genome-wide significant loci beyond the ones identified by univariate analyses. Evidence from larger studies suggest that the variants additionally detected by our test are, indeed, associated with lipid levels in humans. In summary, metaUSAT can provide novel insights into the genetic architecture of a common disease or traits.

Dataset Information

A Bayesian hierarchical variable selection prior for pathway-based GWAS using summary statistics.

Publications

A Bayesian hierarchical variable selection prior for pathway-based GWAS using summary statistics.

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