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 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 Tönjes & 12 others Vilmundur 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

22 Citations (Scopus)

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 (US)
Article numbere1005874
JournalPLoS Genetics
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Fingerprint

vascular endothelial growth factors
Genome-Wide Association Study
meta-analysis
Vascular Endothelial Growth Factor A
Meta-Analysis
genome
loci
gene
Genes
genes
Genome
Physiological Phenomena
neurotrophins
genome-wide association study
Angiogenesis Inducing Agents
cardiovascular disease
Nerve Growth Factors
embryonic development
pathology
angiogenesis

ASJC Scopus subject areas

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

Cite this

Choi, S. H., Ruggiero, D., Sorice, R., Song, C., Nutile, T., Vernon Smith, A., ... 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

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. / Choi, Seung Hoan; Ruggiero, Daniela; Sorice, Rossella; Song, Ci; Nutile, Teresa; Vernon Smith, Albert; Concas, Maria Pina; Traglia, Michela; Barbieri, Caterina; Ndiaye, Ndeye Coumba; Stathopoulou, Maria G.; Lagou, Vasiliki; Maestrale, Giovanni Battista; Sala, Cinzia; Debette, Stephanie; Kovacs, Peter; Lind, Lars; Lamont, John; Fitzgerald, Peter; Tönjes, Anke; Gudnason, Vilmundur; Toniolo, Daniela; Pirastu, Mario; Bellenguez, Celine; Vasan, Ramachandran S.; Ingelsson, Erik; Leutenegger, Anne Louise; Johnson, Andrew D.; DeStefano, Anita L.; Visvikis-Siest, Sophie; Seshadri, Sudha; Ciullo, Marina.

In: PLoS Genetics, Vol. 12, No. 2, e1005874, 01.02.2016.

Research output: Contribution to journalArticle

Choi, SH, Ruggiero, D, Sorice, R, Song, C, Nutile, T, Vernon Smith, A, Concas, MP, Traglia, M, Barbieri, C, Ndiaye, NC, Stathopoulou, MG, Lagou, V, Maestrale, GB, Sala, C, Debette, S, Kovacs, P, Lind, L, Lamont, J, Fitzgerald, P, Tönjes, A, Gudnason, V, Toniolo, D, Pirastu, M, Bellenguez, C, Vasan, RS, Ingelsson, E, Leutenegger, AL, Johnson, AD, DeStefano, AL, Visvikis-Siest, S, Seshadri, S & Ciullo, M 2016, 'Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies', PLoS Genetics, vol. 12, no. 2, e1005874. https://doi.org/10.1371/journal.pgen.1005874
Choi, Seung Hoan ; Ruggiero, Daniela ; Sorice, Rossella ; Song, Ci ; Nutile, Teresa ; Vernon Smith, Albert ; Concas, Maria Pina ; Traglia, Michela ; Barbieri, Caterina ; Ndiaye, Ndeye Coumba ; Stathopoulou, Maria G. ; Lagou, Vasiliki ; Maestrale, Giovanni Battista ; Sala, Cinzia ; Debette, Stephanie ; Kovacs, Peter ; Lind, Lars ; Lamont, John ; Fitzgerald, Peter ; Tönjes, Anke ; Gudnason, Vilmundur ; Toniolo, Daniela ; Pirastu, Mario ; Bellenguez, Celine ; Vasan, Ramachandran S. ; Ingelsson, Erik ; Leutenegger, Anne Louise ; Johnson, Andrew D. ; DeStefano, Anita L. ; Visvikis-Siest, Sophie ; Seshadri, Sudha ; Ciullo, Marina. / Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. In: PLoS Genetics. 2016 ; Vol. 12, No. 2.
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T1 - Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

AU - Choi, Seung Hoan

AU - Ruggiero, Daniela

AU - Sorice, Rossella

AU - Song, Ci

AU - Nutile, Teresa

AU - Vernon Smith, Albert

AU - Concas, Maria Pina

AU - Traglia, Michela

AU - Barbieri, Caterina

AU - Ndiaye, Ndeye Coumba

AU - Stathopoulou, Maria G.

AU - Lagou, Vasiliki

AU - Maestrale, Giovanni Battista

AU - Sala, Cinzia

AU - Debette, Stephanie

AU - Kovacs, Peter

AU - Lind, Lars

AU - Lamont, John

AU - Fitzgerald, Peter

AU - Tönjes, Anke

AU - Gudnason, Vilmundur

AU - Toniolo, Daniela

AU - Pirastu, Mario

AU - Bellenguez, Celine

AU - Vasan, Ramachandran S.

AU - Ingelsson, Erik

AU - Leutenegger, Anne Louise

AU - Johnson, Andrew D.

AU - DeStefano, Anita L.

AU - Visvikis-Siest, Sophie

AU - Seshadri, Sudha

AU - Ciullo, Marina

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

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