title: Expression quantitative trait Loci acting across multiple tissues are enriched in inherited risk for coronary artery disease.
abstract: BACKGROUND
  Despite recent discoveries of new genetic risk factors, the majority of risk for coronary artery disease (CAD) remains elusive. As the most proximal sensor of DNA variation, RNA abundance can help identify subpopulations of genetic variants active in and across tissues mediating CAD risk through gene expression.
  
  
  RESULTS
  By generating new genomic data on DNA and RNA samples from the Stockholm Atherosclerosis Gene Expression (STAGE) study, 8156 cis-acting expression quantitative trait loci (eQTLs) for 6450 genes across 7 CAD-relevant tissues were detected. The inherited risk enrichments of tissue-defined sets of these eQTLs were assessed using 2 independent genome-wide association data sets. eQTLs acting across increasing numbers of tissues were found increasingly enriched for CAD risk and resided at regulatory hot spots. The risk enrichment of 42 eQTLs acting across 5 to 6 tissues was particularly high (≤7.3-fold) and confirmed in the combined genome-wide association data from Coronary Artery Disease Genome Wide Replication And Meta-Analysis Consortium. Sixteen of the 42 eQTLs associated with 19 master regulatory genes and 29 downstream gene sets (n>30) were further risk enriched comparable to that of the 153 genome-wide association risk single-nucleotide polymorphisms established for CAD (8.4-fold versus 10-fold). Three gene sets, governed by the master regulators FLYWCH1, PSORSIC3, and G3BP1, segregated the STAGE patients according to extent of CAD, and small interfering RNA targeting of these master regulators affected cholesterol-ester accumulation in foam cells of the THP1 monocytic cell line.
  
  
  CONCLUSIONS
  eQTLs acting across multiple tissues are significant carriers of inherited risk for CAD. FLYWCH1, PSORSIC3, and G3BP1 are novel master regulatory genes in CAD that may be suitable targets.
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi Asl
authors.forename: Husain A
authors.initials: HA
authors.lastname: Talukdar
authors.forename: Alida S D
authors.initials: AS
authors.lastname: Kindt
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Jain
authors.forename: Raili
authors.initials: R
authors.lastname: Ermel
authors.forename: Arno
authors.initials: A
authors.lastname: Ruusalepp
authors.forename: Khanh-Dung H
authors.initials: KD
authors.lastname: Nguyen
authors.forename: Radu
authors.initials: R
authors.lastname: Dobrin
authors.forename: Dermot F
authors.initials: DF
authors.lastname: Reilly
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Ingrid
authors.initials: I
authors.lastname: Braenne
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Jianlong
authors.initials: J
authors.lastname: Qi
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Ivert
authors.forename: Josefin
authors.initials: J
authors.lastname: Skogsberg
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Tom
authors.initials: T
authors.lastname: Michoel
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
mesh_terms: D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism*; D030541:Databases, Genetic; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D040641:Quantitative Trait Loci
chemical_list: D009124:Muscle Proteins
keywords: coronary artery disease; expression quantitative trait locus; genetics