title: The impact of structural variation on human gene expression.
abstract: Structural variants (SVs) are an important source of human genetic diversity, but their contribution to traits, disease and gene regulation remains unclear. We mapped cis expression quantitative trait loci (eQTLs) in 13 tissues via joint analysis of SVs, single-nucleotide variants (SNVs) and short insertion/deletion (indel) variants from deep whole-genome sequencing (WGS). We estimated that SVs are causal at 3.5-6.8% of eQTLs-a substantially higher fraction than prior estimates-and that expression-altering SVs have larger effect sizes than do SNVs and indels. We identified 789 putative causal SVs predicted to directly alter gene expression: most (88.3%) were noncoding variants enriched at enhancers and other regulatory elements, and 52 were linked to genome-wide association study loci. We observed a notable abundance of rare high-impact SVs associated with aberrant expression of nearby genes. These results suggest that comprehensive WGS-based SV analyses will increase the power of common- and rare-variant association studies.
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Colby
authors.initials: C
authors.lastname: Chiang
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Alexandra J
authors.identifier: http://orcid.org/0000-0002-1930-9265
authors.initials: AJ
authors.lastname: Scott
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joe R
authors.initials: JR
authors.lastname: Davis
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Biomedical Informatics Program, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Emily K
authors.identifier: http://orcid.org/0000-0001-7287-6448
authors.initials: EK
authors.lastname: Tsang
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Yungil
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Tarik
authors.initials: T
authors.lastname: Hadzic
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Farhan N
authors.initials: FN
authors.lastname: Damani
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Liron
authors.identifier: http://orcid.org/0000-0002-8762-622X
authors.initials: L
authors.lastname: Ganel
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.|Department of Computer Science, Stanford University, Stanford, California, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Alexis
authors.identifier: http://orcid.org/0000-0002-5287-627X
authors.initials: A
authors.lastname: Battle
authors.affiliation: Department of Pathology &Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Donald F
authors.identifier: http://orcid.org/0000-0003-3828-8970
authors.initials: DF
authors.lastname: Conrad
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pathology &Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Hall
mesh_terms: D000465:Algorithms; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D054643:INDEL Mutation; D016014:Linear Models; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*