Dataset Information

PolarMorphism enables discovery of shared genetic variants across multiple traits from GWAS summary statistics.

ABSTRACT:

Motivation

Pleiotropic SNPs are associated with multiple traits. Such SNPs can help pinpoint biological processes with an effect on multiple traits or point to a shared etiology between traits. We present PolarMorphism, a new method for the identification of pleiotropic SNPs from genome-wide association studies (GWAS) summary statistics. PolarMorphism can be readily applied to more than two traits or whole trait domains. PolarMorphism makes use of the fact that trait-specific SNP effect sizes can be seen as Cartesian coordinates and can thus be converted to polar coordinates r (distance from the origin) and theta (angle with the Cartesian x-axis, in the case of two traits). r describes the overall effect of a SNP, while theta describes the extent to which a SNP is shared. r and theta are used to determine the significance of SNP sharedness, resulting in a P-value per SNP that can be used for further analysis.

Results

We apply PolarMorphism to a large collection of publicly available GWAS summary statistics enabling the construction of a pleiotropy network that shows the extent to which traits share SNPs. We show how PolarMorphism can be used to gain insight into relationships between traits and trait domains and contrast it with genetic correlation. Furthermore, pathway analysis of the newly discovered pleiotropic SNPs demonstrates that analysis of more than two traits simultaneously yields more biologically relevant results than the combined results of pairwise analysis of the same traits. Finally, we show that PolarMorphism is more efficient and more powerful than previously published methods.

Availability and implementation

code: https://github.com/UMCUGenetics/PolarMorphism, results: 10.5281/zenodo.5844193.

Supplementary information

Supplementary data are available at Bioinformatics online.

SUBMITTER: von Berg J

PROVIDER: S-EPMC9235478 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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.