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

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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=5.75x10-50), 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.

Detaljer

Författare
  • Anke Tönjes
  • Markus Scholz
  • Jacqueline Krüger
  • Kerstin Krause
  • Dorit Schleinitz
  • Holger Kirsten
  • Claudia Gebhardt
  • Carola Marzi
  • Harald Grallert
  • Claes Ladenvall
  • Henrike Heyne
  • Jennifer Kriebel
  • Christa Meisinger
  • Wolfgang Rathmann
  • Christian Gieger
  • 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
Enheter & grupper
Externa organisationer
  • Helmholtz Zentrum München
  • German Center for Diabetes Research
  • Skåne University Hospital
  • Heinrich Heine University Düsseldorf
  • Wellcome Trust Centre for Human Genetics
  • University of Oxford
  • Imperial College London
  • Folkhälsans forskningscentrum
  • Charité Universitätsmedizin Berlin
  • German Institute of Human Nutrition
  • University Hospital Leipzig
  • Leipzig University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
  • Endokrinologi och diabetes
Originalspråkengelska
Sidor (från-till)546-558
TidskriftHuman Molecular Genetics
Volym27
Utgivningsnummer3
StatusPublished - 2018 feb 1
PublikationskategoriForskning
Peer review utfördJa