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Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma

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 a... Full description

Journal Title: American journal of human genetics 2010, Vol.87 (6), p.890-897
Main Author: Carrasquillo, Minerva M
Other Authors: 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, Julia E , Dillman, Allissa , Hernandez, Dena , Petersen, Ronald C , Graff-Radford, Neill R , Younkin, Steven G , Rademakers, Rosa
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Cambridge, MA: Elsevier Inc
ID: ISSN: 0002-9297
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2997361
title: Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma
format: Article
creator:
  • 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, Julia E
  • Dillman, Allissa
  • Hernandez, Dena
  • Petersen, Ronald C
  • Graff-Radford, Neill R
  • Younkin, Steven G
  • Rademakers, Rosa
subjects:
  • Adaptor Proteins, Vesicular Transport - genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Biological and medical sciences
  • Brain
  • Brain-derived neurotrophic factor
  • Care and treatment
  • Cells
  • Chromosome Mapping
  • Chromosomes
  • Chromosomes, Human, Pair 1
  • Cohort Studies
  • Frontotemporal Lobar Degeneration - genetics
  • Fundamental and applied biological sciences. Psychology
  • General aspects. Genetic counseling
  • Genetic aspects
  • Genetics
  • Genetics of eukaryotes. Biological and molecular evolution
  • Genetics(clinical)
  • Genome-Wide Association Study
  • Genomics
  • Health aspects
  • Humans
  • Immunoassay
  • Intercellular Signaling Peptides and Proteins - blood
  • Medical genetics
  • Medical sciences
  • Middle Aged
  • Molecular and cellular biology
  • Mutation
  • Neurogenesis
  • Neurological disorders
  • Plasma
  • Polymorphism
  • Polymorphism, Single Nucleotide
  • Progranulins
  • Proguanil
  • Report
ispartof: American journal of human genetics, 2010, Vol.87 (6), p.890-897
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleGenome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma
sourceAlma/SFX Local Collection
creatorCarrasquillo, 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, Julia E ; Dillman, Allissa ; Hernandez, Dena ; Petersen, Ronald C ; Graff-Radford, Neill R ; Younkin, Steven G ; Rademakers, Rosa
creatorcontribCarrasquillo, 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, Julia E ; Dillman, Allissa ; Hernandez, Dena ; Petersen, Ronald C ; Graff-Radford, Neill R ; Younkin, Steven G ; Rademakers, Rosa
descriptionRecent 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.
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subjectAdaptor Proteins, Vesicular Transport - genetics ; Adult ; Aged ; Aged, 80 and over ; Biological and medical sciences ; Brain ; Brain-derived neurotrophic factor ; Care and treatment ; Cells ; Chromosome Mapping ; Chromosomes ; Chromosomes, Human, Pair 1 ; Cohort Studies ; Frontotemporal Lobar Degeneration - genetics ; Fundamental and applied biological sciences. Psychology ; General aspects. Genetic counseling ; Genetic aspects ; Genetics ; Genetics of eukaryotes. Biological and molecular evolution ; Genetics(clinical) ; Genome-Wide Association Study ; Genomics ; Health aspects ; Humans ; Immunoassay ; Intercellular Signaling Peptides and Proteins - blood ; Medical genetics ; Medical sciences ; Middle Aged ; Molecular and cellular biology ; Mutation ; Neurogenesis ; Neurological disorders ; Plasma ; Polymorphism ; Polymorphism, Single Nucleotide ; Progranulins ; Proguanil ; Report
ispartofAmerican journal of human genetics, 2010, Vol.87 (6), p.890-897
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02010 The American Society of Human Genetics
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1Nicholson, Alexandra M
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5Rutherford, Nicola J
6Hunter, Talisha A
7DeJesus-Hernandez, Mariely
8Bisceglio, Gina D
9Mackenzie, Ian R
10Singleton, Andrew
11Cookson, Mark R
12Crook, Julia E
13Dillman, Allissa
14Hernandez, Dena
15Petersen, Ronald C
16Graff-Radford, Neill R
17Younkin, Steven G
18Rademakers, Rosa
title
0Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma
1American journal of human genetics
addtitleAm J Hum Genet
descriptionRecent 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.
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2Aged
3Aged, 80 and over
4Biological and medical sciences
5Brain
6Brain-derived neurotrophic factor
7Care and treatment
8Cells
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10Chromosomes
11Chromosomes, Human, Pair 1
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13Frontotemporal Lobar Degeneration - genetics
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19Genetics(clinical)
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31Neurogenesis
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11Cookson, Mark R
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titleGenome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma
authorCarrasquillo, 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, Julia E ; Dillman, Allissa ; Hernandez, Dena ; Petersen, Ronald C ; Graff-Radford, Neill R ; Younkin, Steven G ; Rademakers, Rosa
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1Adult
2Aged
3Aged, 80 and over
4Biological and medical sciences
5Brain
6Brain-derived neurotrophic factor
7Care and treatment
8Cells
9Chromosome Mapping
10Chromosomes
11Chromosomes, Human, Pair 1
12Cohort Studies
13Frontotemporal Lobar Degeneration - genetics
14Fundamental and applied biological sciences. Psychology
15General aspects. Genetic counseling
16Genetic aspects
17Genetics
18Genetics of eukaryotes. Biological and molecular evolution
19Genetics(clinical)
20Genome-Wide Association Study
21Genomics
22Health aspects
23Humans
24Immunoassay
25Intercellular Signaling Peptides and Proteins - blood
26Medical genetics
27Medical sciences
28Middle Aged
29Molecular and cellular biology
30Mutation
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7DeJesus-Hernandez, Mariely
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11Cookson, Mark R
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13Dillman, Allissa
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abstractRecent 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.
copCambridge, MA
pubElsevier Inc
pmid21087763
doi10.1016/j.ajhg.2010.11.002
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