A meta-analysis of genome-wide association studies of growth differentiation factor-15 concentration in blood

Jiyang Jiang, Anbupalam Thalamuthu, Jennifer E. Ho, Anubha Mahajan, Weronica E. Ek, David A. Brown, Samuel N. Breit, Thomas J. Wang, Ulf Gyllensten, Ming Huei Chen, Stefan Enroth, James L. Januzzi, Lars Lind, Nicola J. Armstrong, John B. Kwok, Peter R. Schofield, Wei Wen, Julian N. Trollor, Åsa Johansson, Andrew P. MorrisRamachandran S. Vasan, Perminder S. Sachdev, Karen A. Mather

Research output: Contribution to journalArticle

Abstract

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ~5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the"COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

Original languageEnglish (US)
Article number97
JournalFrontiers in Genetics
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 23 2018
Externally publishedYes

Keywords

  • Chromosome 19
  • Community-based individuals
  • Genome-wide association study
  • Growth differentiation factor-15
  • Macrophage inhibitory cytokine-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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    Jiang, J., Thalamuthu, A., Ho, J. E., Mahajan, A., Ek, W. E., Brown, D. A., Breit, S. N., Wang, T. J., Gyllensten, U., Chen, M. H., Enroth, S., Januzzi, J. L., Lind, L., Armstrong, N. J., Kwok, J. B., Schofield, P. R., Wen, W., Trollor, J. N., Johansson, Å., ... Mather, K. A. (2018). A meta-analysis of genome-wide association studies of growth differentiation factor-15 concentration in blood. Frontiers in Genetics, 9(MAR), [97]. https://doi.org/10.3389/fgene.2018.00097