Expression Quantitative Trait Loci Acting Across Multiple Tissues Are Enriched in Inherited Risk for Coronary Artery Disease

CARDIoGRAM Consortium, Hassan Foroughi Asl, Husain A Talukdar, Alida S D Kindt, Rajeev K Jain, Raili Ermel, Arno Ruusalepp, Khanh-Dung H Nguyen, Radu Dobrin, Dermot F Reilly, Heribert Schunkert, Nilesh J Samani, Ingrid Brænne, Jeanette Erdmann, Olle Melander, Jianlong Qi, Torbjörn Ivert, Josefin Skogsberg, Eric E Schadt, Tom MichoelJohan L M Björkegren

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

METHODS AND RESULTS: -By generating new genomic data on DNA and RNA samples from the Stockholm Atherosclerosis Gene Expression (STAGE) study, 8,156 cis-acting expression quantitative trait loci (eQTLs) for 6,450 genes across seven CAD-relevant tissues were detected. The inherited risk-enrichments of tissue-defined sets of these eQTLs were assessed using two independent genome-wide association (GWA) datasets. eQTLs acting across increasing numbers of tissues were found increasingly enriched for CAD risk and resided at regulatory hot spots. The risk-enrichment of forty-two eQTLs acting across 5-6 tissues was particularly high (≤7.3-fold) and confirmed in the combined GWA data from CARDIoGRAM Consortium. Sixteen of the 42 eQTLs associated with 19 master regulatory genes and 29 down-stream gene sets (n>30) were further risk-enriched, comparable to that of the 153 GWA risk SNPs established for CAD (8.4 vs. 10-fold). Three gene sets, governed by the master regulators FLYWCH1, PSORSIC3, and G3BP1, segregated the STAGE patients according to extent of CAD and siRNA targeting of these master regulators affected cholesterol-ester accumulation in THP1-foam cells.

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.

Original languageEnglish
JournalCirculation: Cardiovascular Genetics
Publication statusPublished - 11 Jan 2015


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