title: Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells.
abstract: In this study, we used whole-genome sequencing and gene expression profiling of 215 human induced pluripotent stem cell (iPSC) lines from different donors to identify genetic variants associated with RNA expression for 5,746 genes. We were able to predict causal variants for these expression quantitative trait loci (eQTLs) that disrupt transcription factor binding and validated a subset of them experimentally. We also identified copy-number variant (CNV) eQTLs, including some that appear to affect gene expression by altering the copy number of intergenic regulatory regions. In addition, we were able to identify effects on gene expression of rare genic CNVs and regulatory single-nucleotide variants and found that reactivation of gene expression on the X chromosome depends on gene chromosomal position. Our work highlights the value of iPSCs for genetic association analyses and provides a unique resource for investigating the genetic regulation of gene expression in pluripotent cells.
authors.affiliation: Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: DeBoever
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093-0419, USA; Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jakubosky
authors.affiliation: Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Benaglio
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Reyna
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA; Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Olson
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093-0419, USA; Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Human Longevity, San Diego, CA 92121, USA.
authors.forename: William
authors.initials: W
authors.lastname: Biggs
authors.affiliation: Human Longevity, San Diego, CA 92121, USA.
authors.forename: Efren
authors.initials: E
authors.lastname: Sandoval
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: D'Antonio
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Arias
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA; Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nariai
authors.affiliation: Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Smith
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: D'Antonio-Chronowska
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA; Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, CA 92093-0419, USA. Electronic address: efarley@ucsd.edu.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Farley
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0419, USA; Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093-0419, USA. Electronic address: kafrazer@ucsd.edu.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
mesh_terms: D001665:Binding Sites / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D058977:Molecular Sequence Annotation; D040641:Quantitative Trait Loci / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: eQTL; expression quantitative trait loci; gene expression; regulation of gene expression; stem cell gene expression; stem cell genetics