TY - JOUR
T1 - Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants
AU - Einson, Jonah
AU - Glinos, Dafni
AU - Boerwinkle, Eric
AU - Castaldi, Peter
AU - Darbar, Dawood
AU - De Andrade, Mariza
AU - Ellinor, Patrick
AU - Fornage, Myriam
AU - Gabriel, Stacey
AU - Germer, Soren
AU - Gibbs, Richard
AU - Hersh, Craig P.
AU - Johnsen, Jill
AU - Kaplan, Robert
AU - Konkle, Barbara A.
AU - Kooperberg, Charles
AU - Nassir, Rami
AU - Loos, Ruth J.F.
AU - Meyers, Deborah A.
AU - Mitchell, Braxton D.
AU - Psaty, Bruce
AU - Vasan, Ramachandran S.
AU - Rich, Stephen S.
AU - Rienstra, Michael
AU - Rotter, Jerome I.
AU - Saferali, Aabida
AU - Shoemaker, Moore Benjamin
AU - Silverman, Edwin
AU - Smith, Albert Vernon
AU - Mohammadi, Pejman
AU - Castel, Stephane E.
AU - Iossifov, Ivan
AU - Lappalainen, Tuuli
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved.
PY - 2023/8
Y1 - 2023/8
N2 - 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-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing 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.
AB - 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-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing 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.
KW - GTEx
KW - QTLs
KW - Simons Simplex Collection
KW - TOPMed
KW - alternative splicing
KW - functional genomics
KW - incomplete penetrance
KW - statistical genetics
UR - http://www.scopus.com/inward/record.url?scp=85167482311&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85167482311&partnerID=8YFLogxK
U2 - 10.1093/genetics/iyad115
DO - 10.1093/genetics/iyad115
M3 - Article
C2 - 37348055
AN - SCOPUS:85167482311
SN - 0016-6731
VL - 224
JO - Genetics
JF - Genetics
IS - 4
M1 - iyad115
ER -