ADELLE: A global testing method for trans-eQTL mapping.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Quantitative Trait Loci* ; Polymorphism, Single Nucleotide*/genetics ; Chromosome Mapping*/methods; Mice ; Animals ; Genome-Wide Association Study/methods ; Humans ; Gene Expression Regulation ; Computer Simulation

Understanding the genetic regulatory mechanisms of gene expression is an ongoing challenge. Genetic variants that are associated with expression levels are readily identified when they are proximal to the gene (i.e., cis-eQTLs), but SNPs distant from the gene whose expression levels they are associated with (i.e., trans-eQTLs) have been much more difficult to discover, even though they account for a majority of the heritability in gene expression levels. A major impediment to the identification of more trans-eQTLs is the lack of statistical methods that are powerful enough to overcome the obstacles of small effect sizes and large multiple testing burden of trans-eQTL mapping. Here, we propose ADELLE, a powerful statistical testing framework that requires only summary statistics and is designed to be most sensitive to SNPs that are associated with multiple gene expression levels, a characteristic of many trans-eQTLs. In simulations, we show that for detecting SNPs that are associated with 0.1%-2% of 10,000 traits, among the 8 methods we consider ADELLE is clearly the most powerful overall, with either the highest power or power not significantly different from the highest for all settings in that range. We apply ADELLE to a mouse advanced intercross line data set and show its ability to find trans-eQTLs that were not significant under a standard analysis. We also apply ADELLE to trans-eQTL mapping in the eQTLGen data, and for 1,451 previously identified trans-eQTLs, we discover trans association with additional expression traits beyond those previously identified. This demonstrates that ADELLE is a powerful tool at uncovering trans regulators of genetic expression.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2025 Akinbiyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Update of: bioRxiv. 2024 Jul 16:2024.02.24.581871. doi: 10.1101/2024.02.24.581871. (PMID: 38464248)

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R01 HG001645 United States HG NHGRI NIH HHS

Date Created: 20250110 Date Completed: 20250123 Latest Revision: 20250129

20250129

PMC11756770

10.1371/journal.pgen.1011563

39792937