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, Juliana Crook, Allissa Dillman, Dena Hernandez, Ronald Carl Petersen, Neill R Graff Radford, Steven G Younkin, Rosa V Rademakers

Research output: Contribution to journalArticle

85 Citations (Scopus)

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

Single Nucleotide Polymorphism
Genome
Frontotemporal Lobar Degeneration
Neurodegenerative Diseases
Mutation
Chromosomes
Alleles
Genome-Wide Association Study
Nerve Growth Factors
Conditioned Culture Medium
HeLa Cells
Dementia
Cultured Cells
Enzyme-Linked Immunosorbent Assay
sortilin
Messenger RNA
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. / Carrasquillo, Minerva M; Nicholson, Alexandra M.; Finch, Nicole; Gibbs, J. Raphael; Baker, Matt; Rutherford, Nicola J.; Hunter, Talisha A.; Dejesus-Hernandez, Mariely; Bisceglio, Gina D.; MacKenzie, Ian R.; Singleton, Andrew; Cookson, Mark R.; Crook, Juliana; Dillman, Allissa; Hernandez, Dena; Petersen, Ronald Carl; Graff Radford, Neill R; Younkin, Steven G; Rademakers, Rosa V.

In: American Journal of Human Genetics, Vol. 87, No. 6, 10.12.2010, p. 890-897.

Research output: Contribution to journalArticle

Carrasquillo, MM, Nicholson, AM, Finch, N, Gibbs, JR, Baker, M, Rutherford, NJ, Hunter, TA, Dejesus-Hernandez, M, Bisceglio, GD, MacKenzie, IR, Singleton, A, Cookson, MR, Crook, J, Dillman, A, Hernandez, D, Petersen, RC, Graff Radford, NR, Younkin, SG & Rademakers, RV 2010, 'Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma', American Journal of Human Genetics, vol. 87, no. 6, pp. 890-897. https://doi.org/10.1016/j.ajhg.2010.11.002
Carrasquillo, Minerva M ; Nicholson, Alexandra M. ; Finch, Nicole ; Gibbs, J. Raphael ; Baker, Matt ; Rutherford, Nicola J. ; Hunter, Talisha A. ; Dejesus-Hernandez, Mariely ; Bisceglio, Gina D. ; MacKenzie, Ian R. ; Singleton, Andrew ; Cookson, Mark R. ; Crook, Juliana ; Dillman, Allissa ; Hernandez, Dena ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Younkin, Steven G ; Rademakers, Rosa V. / Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. In: American Journal of Human Genetics. 2010 ; Vol. 87, No. 6. pp. 890-897.
@article{5a81d69b142e44d0a7ef8ceda399cff8,
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.",
author = "Carrasquillo, {Minerva M} and Nicholson, {Alexandra M.} and Nicole Finch and Gibbs, {J. Raphael} and Matt Baker and Rutherford, {Nicola J.} and Hunter, {Talisha A.} and Mariely Dejesus-Hernandez and Bisceglio, {Gina D.} and MacKenzie, {Ian R.} and Andrew Singleton and Cookson, {Mark R.} and Juliana Crook and Allissa Dillman and Dena Hernandez and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Younkin, {Steven G} and Rademakers, {Rosa V}",
year = "2010",
month = "12",
day = "10",
doi = "10.1016/j.ajhg.2010.11.002",
language = "English (US)",
volume = "87",
pages = "890--897",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma

AU - Carrasquillo, Minerva M

AU - Nicholson, Alexandra M.

AU - Finch, Nicole

AU - Gibbs, J. Raphael

AU - Baker, Matt

AU - Rutherford, Nicola J.

AU - Hunter, Talisha A.

AU - Dejesus-Hernandez, Mariely

AU - Bisceglio, Gina D.

AU - MacKenzie, Ian R.

AU - Singleton, Andrew

AU - Cookson, Mark R.

AU - Crook, Juliana

AU - Dillman, Allissa

AU - Hernandez, Dena

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Younkin, Steven G

AU - Rademakers, Rosa V

PY - 2010/12/10

Y1 - 2010/12/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78649796276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649796276&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2010.11.002

DO - 10.1016/j.ajhg.2010.11.002

M3 - Article

C2 - 21087763

AN - SCOPUS:78649796276

VL - 87

SP - 890

EP - 897

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -