title: Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma.
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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: NiCole
authors.initials: N
authors.lastname: Finch
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Talisha A
authors.initials: TA
authors.lastname: Hunter
authors.forename: Mariely
authors.initials: M
authors.lastname: DeJesus-Hernandez
authors.forename: Gina D
authors.initials: GD
authors.lastname: Bisceglio
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.forename: Allissa
authors.initials: A
authors.lastname: Dillman
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D015331:Cohort Studies; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D000099183:Sortilin; C492314:GRN protein, human