Abstract
Countering prior beliefs that epistasis is rare, genomics advancements suggest the other way. Current practice often filters out genomic loci with low variant counts before detecting epistasis. We argue that this practice is far from optimal because it can throw away strong epistatic patterns. Instead, we present the compensated Sharma–Song test to infer genetic epistasis in genome-wide association studies by differential departure from independence. The test does not require a minimum number of replicates for each variant. We also introduce algorithms to simulate epistatic patterns that differentially depart from independence. Using two simulators, the test performed comparably to the original Sharma–Song test when variant frequencies at a locus are marginally uniform; encouragingly, it has a marked advantage over alternatives when variant frequencies are marginally nonuniform. The test further revealed uniquely clean epistatic variants associated with chicken abdominal fat content that are not prioritized by other methods. Genes involved in most numbers of inferred epistasis between single nucleotide polymorphisms (SNPs) belong to pathways known for obesity regulation; many top SNPs are located on chromosome 20 and in intergenic regions. Measuring differential departure from independence, the compensated Sharma–Song test offers a practical choice for studying epistasis robust to nonuniform genetic variant frequencies.
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Data and code availability
The compensated Sharma–Song test and the differential table simulation algorithms are implemented in the open-source R package ‘DiffXTables’ (Sharma and Song 2021) freely available from https://cran.r-project.org/package=DiffXTables. Data and other source code are available at Code Ocean doi: https://doi.org/10.24433/CO.7661508.v1.
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Acknowledgements
This reported work was partially supported by National Science Foundation Grant 1661331 and USDA grant 2016-51181-25408.
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Sharma, R., Sadeghian Tehrani, Z., Kumar, S. et al. Detecting genetic epistasis by differential departure from independence. Mol Genet Genomics 297, 911–924 (2022). https://doi.org/10.1007/s00438-022-01893-3
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DOI: https://doi.org/10.1007/s00438-022-01893-3