1. Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases
- Author
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Josefin Skogsberg, Antonio Fabio Di Narzo, Hassan Foroughi-Asl, Sulev Kõks, Johan Björkegren, Bojan Losic, Chiara Giannarelli, Li-Ming Gan, John F. Fullard, Claudia Giambartolomei, Oscar Franzén, Tom Michoel, Husain A. Talukdar, Raili Ermel, Jason C. Kovacic, Panos Roussos, Ke Hao, Eric E. Schadt, Katyayani Sukhavasi, Arno Ruusalepp, Ariella Cohain, Nicholas K. Akers, and Christer Betsholtz
- Subjects
Male ,Risk ,0301 basic medicine ,Quantitative Trait Loci ,Abdominal Fat ,Single-nucleotide polymorphism ,Genome-wide association study ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Quantitative trait locus ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Polymorphism (computer science) ,medicine ,Humans ,Gene Regulatory Networks ,Muscle, Skeletal ,Genetic association ,Regulation of gene expression ,Genetics ,Multidisciplinary ,PCSK9 ,Serine Endopeptidases ,Cholesterol, LDL ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Liver ,Organ Specificity ,Female ,Proprotein Convertases ,Proprotein Convertase 9 ,Genome-Wide Association Study - 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.
- Published
- 2016
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