Diabetologie und Stoffwechsel 2016; 11 - P169
DOI: 10.1055/s-0036-1580916

Genome wide meta-analysis identifies novel regulators of circulating serum progranulin

J Krüger 1, M Scholz 2, 3, A Gross 2, 3, K Krause 4, C Marzi 5, 6, 7, H Grallert 5, 6, 7, C Ladenvall 8, D Schleinitz 1, H Kirsten 2, 3, 9, H Heyne 1, E Laurila 10, J Kriebel 5, 6, 7, B Thorand 6, 11, W Rathmann 12, L Groop 10, I Prokopenko 13, 14, 15, B Isomaa 16, 17, F Beutner 18, J Kratzsch 18, J Thiery 18, N Klöting 1, 4, A Fischer-Rosinský 19, A Pfeiffer 19, 20, J Spranger 19, C Gieger 21, M Blüher 1, 4, M Stumvoll 1, 4, P Kovacs 1, 4, A Tönjes 4
  • 1Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany
  • 2Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 3LIFE Research Center, University of Leipzig, Leipzig, Germany
  • 4Department of Medicine, University of Leipzig, Leipzig, Germany
  • 5Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
  • 6Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
  • 7German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
  • 8Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  • 9Department for Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
  • 10Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö, Sweden
  • 11Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany
  • 12Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  • 13Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
  • 14Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
  • 15Department of Genomics of Common Diseases, Imperial College London, London, United Kingdom
  • 16Department of Social Services and Health Care, Jakobstad, Finland
  • 17Folkhälsan Research Centre, Helsinki, Finland
  • 18Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
  • 19Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • 20Department of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal, Germany
  • 21Institute of Genetic Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

Background: Progranulin is a secreted protein with important functions in processes including immune and inflammatory response and embryonic development. Genetic factors determining progranulin concentrations are yet unknown.

Material and methods: We conducted a meta-analysis of genome-wide association studies (GWAS) for serum progranulin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). All SNPs associated with progranulin levels were genotyped for replication in 2 additional cohorts: LIFE Heart Study (N = 967) and Berlin cohort (Metabolic Syndrome Berlin Potsdam; N = 794). In addition, we measured mRNA expression of genes within the associated loci in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to elucidate the role of associated genes on progranulin secretion.

Results: Heritability estimate of circulating progranulin levels was 31.8% in the Sorbs cohort. Nine single nucleotide polymorphisms (SNPs) at chromosome 1 within the CELSR2-PSRC1-MYBPHL locus reached genome-wide significance (p < 5.0 × 10-8) in the meta-analysis (the strongest evidence for association at rs660240 (p = 3.98 × 10-15, beta =-0.161). All other SNPs within the cluster were in linkage disequilibrium with rs660240 (r2= 0.8 in the Sorbs cohort). Rs660240 was associated with mRNA expression of PSRC1 in peripheral blood mononuclear cells (p = 1.51 × 10-21). Psrc1 knock-down in murine 3T3-L1 preadipocytes led to a consecutive 30% reduction in progranulin secretion.

Conclusion: In conclusion, the present meta-GWAS combined with mRNA expression and in vitro functional studies highlight the role of PSRC1 in the regulation of circulating progranulin.