title: Mapping cis- and trans-regulatory effects across multiple tissues in twins.
abstract: Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Åsa K
authors.initials: ÅK
authors.lastname: Hedman
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Sarah
authors.initials: S
authors.lastname: Keildson
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.forename: Eshwar
authors.initials: E
authors.lastname: Meduri
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: James
authors.initials: J
authors.lastname: Nisbett
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sekowska
authors.forename: Alicja
authors.initials: A
authors.lastname: Wilk
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.forename: Mary
authors.initials: M
authors.lastname: Travers
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: Sue
authors.initials: S
authors.lastname: Ring
authors.forename: Karen
authors.initials: K
authors.lastname: Ho
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteindottir
authors.forename: Chrysanthi
authors.initials: C
authors.lastname: Ainali
authors.forename: Antigone S
authors.initials: AS
authors.lastname: Dimas
authors.forename: Neelam
authors.initials: N
authors.lastname: Hassanali
authors.forename: Catherine
authors.initials: C
authors.lastname: Ingle
authors.forename: David
authors.initials: D
authors.lastname: Knowles
authors.forename: Maria
authors.initials: M
authors.lastname: Krestyaninova
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Lowe
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Leopold
authors.initials: L
authors.lastname: Parts
authors.forename: Simon
authors.initials: S
authors.lastname: Potter
authors.forename: Gabriela
authors.initials: G
authors.lastname: Surdulescu
authors.forename: Loukia
authors.initials: L
authors.lastname: Tsaprouni
authors.forename: Sophia
authors.initials: S
authors.lastname: Tsoka
authors.forename: Veronique
authors.initials: V
authors.lastname: Bataille
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.forename: Kourosh R
authors.initials: KR
authors.lastname: Ahmadi
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D005260:Female; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D008040:Genetic Linkage; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008875:Middle Aged; D008957:Models, Genetic; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012867:Skin / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism; D014158:Transcription, Genetic