title: Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.
abstract: Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.|National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Seung Hoan
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ruggiero
authors.affiliation: Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Sorice
authors.affiliation: Population Sciences Branch, National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.|Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ci
authors.initials: C
authors.lastname: Song
authors.affiliation: Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Nutile
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|University of Iceland, Reykjavik, Iceland.
authors.forename: Albert
authors.initials: A
authors.lastname: Vernon Smith
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
authors.forename: Maria Pina
authors.initials: MP
authors.lastname: Concas
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Barbieri
authors.affiliation: UMR INSERM U1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, France.
authors.forename: Ndeye Coumba
authors.initials: NC
authors.lastname: Ndiaye
authors.affiliation: UMR INSERM U1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, France.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Stathopoulou
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Lagou
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Maestrale
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sala
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Department of Neurology, Bordeaux University Hospital, Bordeaux, France.|INSERM U897, Bordeaux, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Debette
authors.affiliation: University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Randox Laboratories, Crumlin, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Lamont
authors.affiliation: Randox Laboratories, Crumlin, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Fitzgerald
authors.affiliation: University of Leipzig, Department of Medicine, Leipzig, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Pirastu
authors.affiliation: Institut Pasteur de Lille, Lille, France.|INSEM U744, Lille, France.|Université Lille-Nord de France, Lille, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Bellenguez
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.|Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, United States of America.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: INSERM U946, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, IUH, UMR-S 946, Paris, France.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Leutenegger
authors.affiliation: Population Sciences Branch, National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.|National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.affiliation: UMR INSERM U1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.|National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ciullo
mesh_terms: D002877:Chromosomes, Human; D015870:Gene Expression; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A