Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

Seung Hoan Choi, Daniela Ruggiero, Rossella Sorice, Ci Song, Teresa Nutile, Albert Vernon Smith, Maria Pina Concas, Michela Traglia, Caterina Maria Barbieri, Ndeye Coumba Ndiaye, Maria G. Stathopoulou, Vasiliki Lagou, Giovanni Battista Maestrale, Cinzia Sala, Stephanie Debette, Peter Kovacs, Lars Lind, John Lamont, Peter Fitzgerald, Anke TönjesVilmundur Gudnason, Daniela Toniolo, Mario Pirastu, Celine Bellenguez, Ramachandran S. Vasan, Erik Ingelsson, Anne Louise Leutenegger, Andrew D. Johnson, Anita L. DeStefano, Sophie Visvikis-Siest, Sudha Seshadri, Marina Ciullo

Research output: Contribution to journalArticle

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 = 6.79x10-13), rs74506613 (JMJD1C, P = 1.17x10-19), rs4782371 (ZFPM1, P = 1.59x10-9) and rs2639990 (ZADH2, P = 1.72x10-8), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10-18; rs7043199, VLDLR-AS1, P = 5.12x10-14) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10-1467; rs1740073, C6orf223, P = 2.34x10-17; rs6993770, ZFPM2, P = 2.44x10-60; rs2375981, KCNV2, P = 1.48x10-100). 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.

Original languageEnglish
Article numbere1005874
JournalPLoS Genetics
Volume12
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies'. Together they form a unique fingerprint.

  • Cite this

    Choi, S. H., Ruggiero, D., Sorice, R., Song, C., Nutile, T., Vernon Smith, A., Concas, M. P., Traglia, M., Barbieri, C. M., Ndiaye, N. C., Stathopoulou, M. G., Lagou, V., Maestrale, G. B., Sala, C., Debette, S., Kovacs, P., Lind, L., Lamont, J., Fitzgerald, P., ... Ciullo, M. (2016). Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. PLoS Genetics, 12(2), [e1005874]. https://doi.org/10.1371/journal.pgen.1005874