title: The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.
abstract: While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Leopold
authors.initials: L
authors.lastname: Parts
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.forename: James
authors.initials: J
authors.lastname: Nisbet
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sekowska
authors.forename: Mary
authors.initials: M
authors.lastname: Travers
authors.forename: Simon
authors.initials: S
authors.lastname: Potter
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Kerrin
authors.initials: K
authors.lastname: Small
authors.forename: Asa K
authors.initials: AK
authors.lastname: Hedman
authors.forename: Veronique
authors.initials: V
authors.lastname: Bataille
authors.forename: Jordana
authors.initials: J
authors.lastname: Tzenova Bell
authors.forename: Gabriela
authors.initials: G
authors.lastname: Surdulescu
authors.forename: Antigone S
authors.initials: AS
authors.lastname: Dimas
authors.forename: Catherine
authors.initials: C
authors.lastname: Ingle
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.forename: Paola
authors.initials: P
authors.lastname: di Meglio
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: Alicja
authors.initials: A
authors.lastname: Wilk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
authors.forename: Neelam
authors.initials: N
authors.lastname: Hassanali
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Steve
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.forename: Kourosh
authors.initials: K
authors.lastname: Ahmadi
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D005260:Female; D020869:Gene Expression Profiling; D005809:Genes, Regulator / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D012867:Skin / Q000378:metabolism*; D014427:Twins