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

J Krüger; M Scholz; A Gross; K Krause; C Marzi; H Grallert; C Ladenvall; D Schleinitz; H Kirsten; H Heyne; E Laurila; J Kriebel; B Thorand; W Rathmann; L Groop; I Prokopenko; B Isomaa; F Beutner; J Kratzsch; J Thiery; N Klöting; A Fischer-Rosinský; A Pfeiffer; J Spranger; C Gieger; M Blüher; M Stumvoll; P Kovacs; A Tönjes

doi:10.1055/s-0036-1580916

Diabetologie und Stoffwechsel, Inhaltsverzeichnis

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

Abstract

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.