title: 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.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Franzén
authors.affiliation: Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406 Tartu, Estonia.
authors.forename: Raili
authors.initials: R
authors.lastname: Ermel
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Ariella
authors.initials: A
authors.lastname: Cohain
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Akers
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Narzo
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden.
authors.forename: Husain A
authors.initials: HA
authors.lastname: Talukdar
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden.
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi-Asl
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Giambartolomei
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Fullard
authors.affiliation: Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia.
authors.forename: Katyayani
authors.initials: K
authors.lastname: Sukhavasi
authors.affiliation: Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia.
authors.forename: Sulev
authors.initials: S
authors.lastname: Köks
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Gan
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Cardiovascular Research Center Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.affiliation: Cardiovascular Research Center Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.affiliation: AstraZeneca-Karolinska Integrated CardioMetabolic Centre (ICMC), Karolinska Institutet, Novum, Blickagången 6, 141 57 Huddinge, Sweden. Department of Immunology, Genetics and Pathology Dag Hammarskjölds Väg 20, 751 85 Uppsala, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Bojan
authors.initials: B
authors.lastname: Losic
authors.affiliation: Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Old College, South Bridge, Edinburgh EH8 9YL, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Michoel
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Department of Psychiatry, J. J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC), 130 West Kingsbridge Road, Bronx, NY 10468, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden.
authors.forename: Josefin
authors.initials: J
authors.lastname: Skogsberg
authors.affiliation: Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406 Tartu, Estonia.
authors.forename: Arno
authors.initials: A
authors.lastname: Ruusalepp
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden. johan.bjorkegren@mssm.edu.
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D040641:Quantitative Trait Loci; D012306:Risk; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases