Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma

Minerva M. Carrasquillo, Alexandra M. Nicholson, Nicole Finch, J. Raphael Gibbs, Matt Baker, Nicola J. Rutherford, Talisha A. Hunter, Mariely Dejesus-Hernandez, Gina D. Bisceglio, Ian R. MacKenzie, Andrew Singleton, Mark R. Cookson, Julia E. Crook, Allissa Dillman, Dena Hernandez, Ronald C. Petersen, Neill R. Graff-Radford, Steven G. Younkin, Rosa Rademakers

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Using an enzyme-linked immunosorbent assay, we previously showed that GRN is detectable in human plasma and can be used to predict GRN mutation status. This study also showed a wide range in plasma GRN levels in non-GRN mutation carriers, including controls. We have now performed a genome-wide association study of 313,504 single-nucleotide polymorphisms (SNPs) in 533 control samples and identified on chromosome 1p13.3 two SNPs with genome-wide significant association with plasma GRN levels (top SNP rs646776; p = 1.7 × 10-30). The association of rs646776 with plasma GRN levels was replicated in two independent series of 508 controls (p = 1.9 × 10-19) and 197 FTLD patients (p = 6.4 × 10-12). Overall, each copy of the minor C allele decreased GRN levels by ∼15%. SNP rs646776 is located near sortilin (SORT1), and the minor C allele of rs646776 was previously associated with increased SORT1 mRNA levels. Supporting these findings, overexpression of SORT1 in cultured HeLa cells dramatically reduced GRN levels in the conditioned media, whereas knockdown of SORT1 increased extracellular GRN levels. In summary, we identified significant association of a locus on chromosome 1p13.3 with plasma GRN levels through an unbiased genome-wide screening approach and implicated SORT1 as an important regulator of GRN levels. This finding opens avenues for future research into GRN biology and the pathophysiology of neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)890-897
Number of pages8
JournalAmerican journal of human genetics
Volume87
Issue number6
DOIs
StatePublished - Dec 10 2010

    Fingerprint

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Carrasquillo, M. M., Nicholson, A. M., Finch, N., Gibbs, J. R., Baker, M., Rutherford, N. J., Hunter, T. A., Dejesus-Hernandez, M., Bisceglio, G. D., MacKenzie, I. R., Singleton, A., Cookson, M. R., Crook, J. E., Dillman, A., Hernandez, D., Petersen, R. C., Graff-Radford, N. R., Younkin, S. G., & Rademakers, R. (2010). Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. American journal of human genetics, 87(6), 890-897. https://doi.org/10.1016/j.ajhg.2010.11.002