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Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.

TitleGenetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.
Publication TypeJournal Article
Year of Publication2023
AuthorsEinson, J, Glinos, D, Boerwinkle, E, Castaldi, P, Darbar, D, de Andrade, M, Ellinor, P, Fornage, M, Gabriel, S, Germer, S, Gibbs, R, Hersh, CP, Johnsen, J, Kaplan, R, Konkle, BA, Kooperberg, C, Nassir, R, Loos, RJF, Meyers, DA, Mitchell, BD, Psaty, B, Vasan, RS, Rich, SS, Rienstra, M, Rotter, JI, Saferali, A, M Shoemaker, B, Silverman, E, Smith, AVernon, Mohammadi, P, Castel, SE, Iossifov, I, Lappalainen, T
Corporate/Institutional AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Date Published2023 Jan 31
Abstract<p>Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.</p>
Alternate JournalbioRxiv
PubMed ID36778406
PubMed Central IDPMC9915611
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