Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin
File(s)
Accepted version
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2018-02-01
Date Acceptance
2017-11-22
Citation
Human Molecular Genetics, 2018, 27 (3), pp.546-558
ISSN
0964-6906
Publisher
Oxford University Press (OUP)
Start Page
546
End Page
558
Journal / Book Title
Human Molecular Genetics
Volume
27
Issue
3
Copyright Statement
© 2017 Oxford University Press. This is a pre-copy-editing, author-produced version of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version, Anke Tönjes, Markus Scholz, Jacqueline Krüger, Kerstin Krause, Dorit Schleinitz, Holger Kirsten, Claudia Gebhardt, Carola Marzi, Harald Grallert, Claes Ladenvall, Henrike Heyne, Esa Laurila, Jennifer Kriebel, Christa Meisinger, Wolfgang Rathmann, Christian Gieger, Leif Groop, Inga Prokopenko, Bo Isomaa, Frank Beutner, Jürgen Kratzsch, Antje Fischer-Rosinsky, Andreas Pfeiffer, Knut Krohn, Joachim Spranger, Joachim Thiery, Matthias Blüher, Michael Stumvoll, Peter Kovacs; Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin, Human Molecular Genetics, Volume 27, Issue 3, 1 February 2018, Pages 546–558, is available online at: https://dx.doi.org/10.1093/hmg/ddx413
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000424136000013&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
FRONTOTEMPORAL LOBAR DEGENERATION
ASSOCIATION ANALYSIS
INSULIN-RESISTANCE
ADIPOSE-TISSUE
GROWTH-FACTOR
TRANS-EQTLS
EXPRESSION
PLASMA
LOCI
DDA3
Publication Status
Published
Date Publish Online
2017-11-27