title: Variants affecting exon skipping contribute to complex traits.
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.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA. younghee@uchicago.edu
authors.forename: Younghee
authors.initials: Y
authors.lastname: Lee
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Ellen
authors.initials: E
authors.lastname: Rebman
authors.forename: Yeunsook
authors.initials: Y
authors.lastname: Lee
authors.forename: Sanghyuk
authors.initials: S
authors.lastname: Lee
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
mesh_terms: D017398:Alternative Splicing; D019295:Computational Biology / Q000379:methods; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000235:genetics; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D008958:Models, Molecular; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D059368:RNA Isoforms
chemical_list: D011506:Proteins; D059368:RNA Isoforms; C501013:CDK10 protein, human; D018844:Cyclin-Dependent Kinases