Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases.

Abstract

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.

• Authors: Oscar Franzén, Raili Ermel, Ariella Cohain, Nicholas K Akers, Antonio Di Narzo, Husain A Talukdar, Hassan Foroughi-Asl, Claudia Giambartolomei, John F Fullard, Katyayani Sukhavasi, Sulev Köks, Li-Ming Gan, Chiara Giannarelli, Jason C Kovacic, Christer Betsholtz, Bojan Losic, Tom Michoel, Ke Hao, Panos Roussos, Josefin Skogsberg, Arno Ruusalepp, Eric E Schadt, Johan L M Björkegren
• Journal: Science (New York, N.Y.) (Science) Vol. 353 Issue 6301 Pg. 827-30 (Aug 19 2016) ISSN: 1095-9203 [Electronic] United States
• PMID: 27540175 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Cholesterol, LDL
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Abdominal Fat (metabolism)
• Alzheimer Disease (genetics)
• Cholesterol, LDL (blood, genetics)
• Coronary Artery Disease (epidemiology, genetics)
• Female
• Gene Expression Regulation
• Gene Regulatory Networks
• Genome-Wide Association Study
• Humans
• Liver (metabolism)
• Male
• Muscle, Skeletal (metabolism)
• Organ Specificity (genetics)
• Polymorphism, Single Nucleotide
• Proprotein Convertase 9
• Proprotein Convertases (genetics)
• Quantitative Trait Loci
• Risk
• Serine Endopeptidases (genetics)