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Hum Mol Genet. 2018 Feb 1;27(3):546-558. doi: 10.1093/hmg/ddx413.

Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.

Author information

1
Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
2
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany.
3
LIFE Research Center, University of Leipzig, Leipzig 04103, Germany.
4
Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig 04103, Germany.
5
Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
6
German Research Center for Environmental Health, Institute of Epidemiology II, Helmholtz Center Munich, Neuherberg 85764, Germany.
7
German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany.
8
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö 20502, Sweden.
9
Institute of Human Genetics, University of Leipzig, Leipzig 04103, Germany.
10
German Diabetes Center, Institute of Biometrics and Epidemiology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany.
11
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
12
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
13
Department of Genomics of Common Diseases, Imperial College London, London SW7 2AZ, UK.
14
Department of Social Services and Healthcare, Jakobstad 68601, Finland.
15
Folkhälsan Research Centre, Helsinki 00290, Finland.
16
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig 04103, Germany.
17
Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin, Berlin 10117, Germany.
18
Department of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal 14558, Germany.
19
Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig 04103, Germany.

Abstract

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes 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 validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

PMID:
29186428
DOI:
10.1093/hmg/ddx413
[Indexed for MEDLINE]
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