TY - JOUR
T1 - A meta-analysis of genome-wide association studies of growth differentiation factor-15 concentration in blood
AU - Jiang, Jiyang
AU - Thalamuthu, Anbupalam
AU - Ho, Jennifer E.
AU - Mahajan, Anubha
AU - Ek, Weronica E.
AU - Brown, David A.
AU - Breit, Samuel N.
AU - Wang, Thomas J.
AU - Gyllensten, Ulf
AU - Chen, Ming Huei
AU - Enroth, Stefan
AU - Januzzi, James L.
AU - Lind, Lars
AU - Armstrong, Nicola J.
AU - Kwok, John B.
AU - Schofield, Peter R.
AU - Wen, Wei
AU - Trollor, Julian N.
AU - Johansson, Åsa
AU - Morris, Andrew P.
AU - Vasan, Ramachandran S.
AU - Sachdev, Perminder S.
AU - Mather, Karen A.
N1 - Funding Information:
We would like to gratefully acknowledge and thank the participants of all participating studies and the research teams. JJ is a John Holden Family Foundation Postdoctoral Research Fellow. JH is supported by NIH Grant K23-HL116780. APM is a Wellcome Trust Senior Fellow in Basic Biomedical Science under award WT098017. Framingham-This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contracts N01-HC-25195 and HHSN268201500001I). PIVUS-PIVUS was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (2013-024), Swedish Research Council (2012-1397, 2012-1727, and 2012-2215), Marianne and Marcus Wallenberg Foundation, County Council of Dalarna, Dalarna University, and Swedish Heart-Lung Foundation (20120197). The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. Genotyping was funded by the Wellcome Trust under awards WT064890 and WT086596. Analysis of genetic data was funded by the Wellcome Trust under awards WT098017 and WT090532. NSPHS-Illumina genotyping, and DNA methylation analyses was performed by the SNP&SEQ Technology Platform in Uppsala, which is supported by Uppsala University, Uppsala University Hospital, Science for Life Laboratory (SciLifeLab)-Uppsala and the Swedish Research Council (Contracts 80576801 and 70374401). MIC-1/GDF-15 measurements in the NSPHS were performed by the Science for life Laboratory Clinical Biomarker facility in Uppsala, Sweden. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under projects b2011203, p2012153 and b2013110. The NSPHS study was funded by the Swedish Medical Research Council (Project Number K2007-66X-20270-01-3) and the Foundation for Strategic Research (SSF). NSPHS as part of EUROSPAN (European Special Populations Research Network) was also supported by European Commission FP6 STRP grant number 01947 (LSHG-CT-2006-01947). This work has also been supported by the Swedish Society for Medical Research (SSMF), Swedish Medical Research Council, the Göran Gustafssons Foundation, the Kjell och Märta Beijers Foundation, the Marcus Borgström Foundation, the Åke Wiberg foundation and the Vleugels Foundation. Sydney MAS-Sydney MAS is supported by a National Health and Medical Research Council (NHMRC)/Australian Research Council Strategic Award (Grant 401162), NHMRC Program grants (350833 and 568969) and a Project grant (1045325). This research was also supported by NHMRC Project grants (510175 and 510124), and the Australian Research Council (DP0774213, DP0773584, and LP0669645)
Publisher Copyright:
© 2018 Jiang, Thalamuthu, Ho, Mahajan, Ek, Brown, Breit, Wang, Gyllensten, Chen, Enroth, Januzzi, Lind, Armstrong, Kwok, Schofield, Wen, Trollor, Johansson, Morris, Vasan, Sachdev and Mather.
PY - 2018/3/23
Y1 - 2018/3/23
N2 - 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.
AB - 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.
KW - Chromosome 19
KW - Community-based individuals
KW - Genome-wide association study
KW - Growth differentiation factor-15
KW - Macrophage inhibitory cytokine-1
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U2 - 10.3389/fgene.2018.00097
DO - 10.3389/fgene.2018.00097
M3 - Article
AN - SCOPUS:85044920475
VL - 9
JO - Frontiers in Genetics
JF - Frontiers in Genetics
SN - 1664-8021
IS - MAR
M1 - 97
ER -