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

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.ORCID: 0000-0002-4477-293X, Kwok, J.B., Schofield, P.R., Wen, W., Trollor, J.N., Johansson, Å., Morris, A.P., Vasan, R.S., Sachdev, P.S. and Mather, K.A. (2018) A meta-analysis of genome-wide association studies of growth differentiation Factor-15 concentration in blood. Frontiers in Genetics, 9 .

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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.

Item Type: Journal Article
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Publisher: Frontiers
Copyright: © 2018 The Authors
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