Variants Affecting Exon Skipping Contribute to Complex Traits

Younghee Lee, Eric R. Gamazon, Ellen Rebman, Yeunsook Lee, Sanghyuk Lee, M. Eileen Dolan, Nancy J. Cox, Yves A Lussier

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs) in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1) experimentally validate our in silico predictions of skipped exons and 2) characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

Original languageEnglish (US)
Article numbere1002998
JournalPLoS Genetics
Volume8
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

Fingerprint

single nucleotide polymorphism
exons
Single Nucleotide Polymorphism
Exons
alternative splicing
Alternative Splicing
polymorphism
etiology
Computer Simulation
human diseases
odds ratio
genetic variation
allele
Alleles
Odds Ratio
alleles
DNA
protein
prediction
gene

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Lee, Y., Gamazon, E. R., Rebman, E., Lee, Y., Lee, S., Dolan, M. E., ... Lussier, Y. A. (2012). Variants Affecting Exon Skipping Contribute to Complex Traits. PLoS Genetics, 8(10), [e1002998]. https://doi.org/10.1371/journal.pgen.1002998

Variants Affecting Exon Skipping Contribute to Complex Traits. / Lee, Younghee; Gamazon, Eric R.; Rebman, Ellen; Lee, Yeunsook; Lee, Sanghyuk; Dolan, M. Eileen; Cox, Nancy J.; Lussier, Yves A.

In: PLoS Genetics, Vol. 8, No. 10, e1002998, 10.2012.

Research output: Contribution to journalArticle

Lee, Y, Gamazon, ER, Rebman, E, Lee, Y, Lee, S, Dolan, ME, Cox, NJ & Lussier, YA 2012, 'Variants Affecting Exon Skipping Contribute to Complex Traits', PLoS Genetics, vol. 8, no. 10, e1002998. https://doi.org/10.1371/journal.pgen.1002998
Lee Y, Gamazon ER, Rebman E, Lee Y, Lee S, Dolan ME et al. Variants Affecting Exon Skipping Contribute to Complex Traits. PLoS Genetics. 2012 Oct;8(10). e1002998. https://doi.org/10.1371/journal.pgen.1002998
Lee, Younghee ; Gamazon, Eric R. ; Rebman, Ellen ; Lee, Yeunsook ; Lee, Sanghyuk ; Dolan, M. Eileen ; Cox, Nancy J. ; Lussier, Yves A. / Variants Affecting Exon Skipping Contribute to Complex Traits. In: PLoS Genetics. 2012 ; Vol. 8, No. 10.
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