TY - JOUR
T1 - Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases
AU - Franzén, Oscar
AU - Ermel, Raili
AU - Cohain, Ariella
AU - Akers, Nicholas K.
AU - Di Narzo, Antonio
AU - Talukdar, Husain A.
AU - Foroughi-Asl, Hassan
AU - Giambartolomei, Claudia
AU - Fullard, John F.
AU - Sukhavasi, Katyayani
AU - Köks, Sulev
AU - Gan, Li Ming
AU - Giannarelli, Chiara
AU - Kovacic, Jason C.
AU - Betsholtz, Christer
AU - Losic, Bojan
AU - Michoel, Tom
AU - Hao, Ke
AU - Roussos, Panos
AU - Skogsberg, Josefin
AU - Ruusalepp, Arno
AU - Schadt, Eric E.
AU - Björkegren, Johan L.M.
N1 - Funding Information:
The STARNET study was supported by the University of Tartu (SP1GVARENG to J.L.M.B.), the Estonian Research Council (ETF grant 8853 to A.R. and J.L.M.B.), the Astra-Zeneca Translational Science Centre-Karolinska Institutet (a joint research program in translational science, to J.L.M.B.), Clinical Gene Networks AB (CGN) as an SME of the FP6/FP7 EU-funded integrated project CVgenes@target (HEALTH-F2-2013-601456), the Leducq transatlantic networks, CAD Genomics (C.G., E.E.S., and J.L.M.B.), Sphingonet (C.B.), the Torsten and Ragnar Soderberg Foundation (C.B.), the Knut and Alice Wallenberg Foundation (C.B.), the American Heart Association (A14SFRN20840000 to J.C.K., E.E.S., and J.L.M.B.), the National Institutes of Health (NIH NHLBI R01HL125863 to J.L.M.B.; NIH NHLBI R01HL71207 to E.E.S.; R01AG050986 to P.R.; NIH NHLBI K23HL111339 to C.G.; NIH NHLBI K08HL111330 to J.C.K.), and the Veterans Affairs (Merit grant BX002395 to P.R.).
PY - 2016/8/19
Y1 - 2016/8/19
N2 - 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 RNAsequenced 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.
AB - 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 RNAsequenced 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.
UR - http://www.scopus.com/inward/record.url?scp=84983472699&partnerID=8YFLogxK
U2 - 10.1126/science.aad6970
DO - 10.1126/science.aad6970
M3 - Article
C2 - 27540175
AN - SCOPUS:84983472699
SN - 0036-8075
VL - 353
SP - 827
EP - 830
JO - Science
JF - Science
IS - 6301
ER -