title: RNA splicing is a primary link between genetic variation and disease.
abstract: Noncoding variants play a central role in the genetics of complex traits, but we still lack a full understanding of the molecular pathways through which they act. We quantified the contribution of cis-acting genetic effects at all major stages of gene regulation from chromatin to proteins, in Yoruba lymphoblastoid cell lines (LCLs). About ~65% of expression quantitative trait loci (eQTLs) have primary effects on chromatin, whereas the remaining eQTLs are enriched in transcribed regions. Using a novel method, we also detected 2893 splicing QTLs, most of which have little or no effect on gene-level expression. These splicing QTLs are major contributors to complex traits, roughly on a par with variants that affect gene expression levels. Our study provides a comprehensive view of the mechanisms linking genetic variation to variation in human gene regulation.
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Yang I
authors.initials: YI
authors.lastname: Li
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: van de Geijn
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Raj
authors.affiliation: Department of Computer Science, Stanford University, Stanford, CA, USA. Department of Radiology, Stanford University, Stanford, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Knowles
authors.affiliation: Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Allegra A
authors.initials: AA
authors.lastname: Petti
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Golan
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA. gilad@uchicago.edu pritch@stanford.edu.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gilad
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA. Department of Biology, Stanford University, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. gilad@uchicago.edu pritch@stanford.edu.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012326:RNA Splicing / Q000235:genetics*
chemical_list: D002843:Chromatin