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Tönjes, A.* ; Scholz, M.* ; Krüger, J.* ; Krause, K.* ; Schleinitz, D.* ; Kirsten, H.* ; Gebhardt, C.* ; Marzi, C. ; Grallert, H. ; Ladenvall, C.* ; Heyne, H.* ; Laurila, E.* ; Kriebel, J. ; Meisinger, C. ; Rathmann, W.* ; Gieger, C. ; Groop, L.* ; Prokopenko, I.* ; Isomaa, B.* ; Beutner, F.* ; Kratzsch, J.* ; Fischer-Rosinsky, A.* ; Pfeiffer, A.* ; Krohn, K.* ; Spranger, J.* ; Thiery, J.* ; Blüher, M.* ; Stumvoll, M.* ; Kovacs, P.*

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

Hum. Mol. Genet. 27, 546-558 (2018)
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© The Author(s) 2017. Published by Oxford University Press. All rights reserved. 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 CELSR 2-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=5.75x10 -50 ), which was also associated with mRNA expression of PSRC1 in PBMC (P=1.51x10 -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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Frontotemporal Lobar Degeneration; Association Analysis; Insulin-resistance; Adipose-tissue; Growth-factor; Trans-eqtls; Expression; Plasma; Loci; Dda3
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 27, Issue: 3, Pages: 546-558 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Independent Research Group Clinical Epidemiology (KEPI)