Journal
SCIENCE
Volume 353, Issue 6301, Pages 827-830Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad6970
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Funding
- University of Tartu [SP1GVARENG]
- Estonian Research Council (ETF) [8853]
- Astra-Zeneca Translational Science Centre-Karolinska Institutet
- Clinical Gene Networks AB (CGN) as an SME of the FP6/FP7 EU [HEALTH-F2-2013-601456]
- Leducq transatlantic networks
- CAD Genomics
- Sphingonet
- Torsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- American Heart Association [A14SFRN20840000]
- National Institutes of Health [NIH NHLBI R01HL125863, NIH NHLBI R01HL71207, R01AG050986, NIH NHLBI K23HL111339, NIH NHLBI K08HL111330]
- Veterans Affairs [BX002395]
- Swedish Research Council [VR-RF1]
- Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX)
- Biotechnology and Biological Sciences Research Council [BBS/E/D/20211551] Funding Source: researchfish
- BBSRC [BBS/E/D/20211551] Funding Source: UKRI
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Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue-and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9. STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.
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