Exploiting pleiotropy to enhance variant discovery with functional false discovery rates.

Andrew J Bass; Chris Wallace

doi:10.1038/s43588-025-00852-3

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Exploiting pleiotropy to enhance variant discovery with functional false discovery rates.

Andrew J Bass·Chris Wallace

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Abstract

The cost of recruiting participants for genome-wide association studies (GWASs) can limit sample sizes and hinder the discovery of genetic variants. Here we introduce the surrogate functional false discovery rate (sfFDR) framework that integrates summary statistics of related traits to increase power. The sfFDR framework provides estimates of FDR quantities such as the functional local FDR and q value, and uses these estimates to derive a functional P value for type I error rate control and a functional local Bayes' factor for post-GWAS analyses. Compared with a standard analysis, sfFDR substantially increased power (equivalent to a 52% increase in sample size) in a study of obesity-related traits from the UK Biobank and discovered eight additional lead SNPs near genes linked to immune-related responses in a rare disease GWAS of eosinophilic granulomatosis with polyangiitis. Collectively, these results highlight the utility of exploiting related traits in both small and large studies.

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Humans Genome-Wide Association Study Genetic Pleiotropy Polymorphism, Single Nucleotide Bayes Theorem Obesity Genetic Predisposition to Disease Genetic Variation Journal Article Research Support, Non-U.S. Gov't

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Andrew J Bass, Chris Wallace. 2025-08-22. Exploiting pleiotropy to enhance variant discovery with functional false discovery rates.. https://doi.org/10.1038/s43588-025-00852-3

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