AUTHOR=Jiang Jiyang , Thalamuthu Anbupalam , Ho Jennifer E. , Mahajan Anubha , Ek Weronica E. , Brown David A. , Breit Samuel N. , Wang Thomas J. , Gyllensten Ulf , Chen Ming-Huei , Enroth Stefan , Januzzi James L. , Lind Lars , Armstrong Nicola J. , Kwok John B. , Schofield Peter R. , Wen Wei , Trollor Julian N. , Johansson Åsa , Morris Andrew P. , Vasan Ramachandran S. , Sachdev Perminder S. , Mather Karen A. TITLE=A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood JOURNAL=Frontiers in Genetics VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00097 DOI=10.3389/fgene.2018.00097 ISSN=1664-8021 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.