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GxEsum: a novel approach to estimate the phenotypic variance explained by genome-wide GxE interaction based on GWAS summary statistics for biobank-scale data.

ABSTRACT: Genetic variation in response to the environment, that is, genotype-by-environment interaction (GxE), is fundamental in the biology of complex traits and diseases. However, existing methods are computationally demanding and infeasible to handle biobank-scale data. Here, we introduce GxEsum, a method for estimating the phenotypic variance explained by genome-wide GxE based on GWAS summary statistics. Through comprehensive simulations and analysis of UK Biobank with 288,837 individuals, we show that GxEsum can handle a large-scale biobank dataset with controlled type I error rates and unbiased GxE estimates, and its computational efficiency can be hundreds of times higher than existing GxE methods.

SUBMITTER: Shin J

PROVIDER: S-EPMC8218431 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Identifying phenotypic correlations between complex traits and diseases can provide useful etiological insights. Restricted access to much individual-level phenotype data makes it difficult to estimate large-scale phenotypic correlation across the human phenome. Two state-of-the-art methods, metaCCA and LD score regression, provide an alternative approach to estimate phenotypic correlation using only genome-wide association study (GWAS) summary results. Here, we present an integrated R toolkit, PhenoSpD, to use LD score regression to estimate phenotypic correlations using GWAS summary statistics and to utilize the estimated phenotypic correlations to inform correction of multiple testing for complex human traits using the spectral decomposition of matrices (SpD). The simulations suggest that it is possible to identify nonindependence of phenotypes using samples with partial overlap; as overlap decreases, the estimated phenotypic correlations will attenuate toward zero and multiple testing correction will be more stringent than in perfectly overlapping samples. Also, in contrast to LD score regression, metaCCA will provide approximate genetic correlations rather than phenotypic correlation, which limits its application for multiple testing correction. In a case study, PhenoSpD using UK Biobank GWAS results suggested 399.6 independent tests among 487 human traits, which is close to the 352.4 independent tests estimated using true phenotypic correlation. We further applied PhenoSpD to an estimated 5,618 pair-wise phenotypic correlations among 107 metabolites using GWAS summary statistics from Kettunen's publication and PhenoSpD suggested the equivalent of 33.5 independent tests for these metabolites. PhenoSpD extends the use of summary-level results, providing a simple and conservative way to reduce dimensionality for complex human traits using GWAS summary statistics. This is particularly valuable in the age of large-scale biobank and consortia studies, where GWAS results are much more accessible than individual-level data.

Dataset Information

GxEsum: a novel approach to estimate the phenotypic variance explained by genome-wide GxE interaction based on GWAS summary statistics for biobank-scale data.

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