Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma
Identifieur interne : 000356 ( Pmc/Corpus ); précédent : 000355; suivant : 000357Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma
Auteurs : 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 RademakersSource :
- American Journal of Human Genetics [ 0002-9297 ] ; 2010.
Abstract
Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (
Url:
DOI: 10.1016/j.ajhg.2010.11.002
PubMed: 21087763
PubMed Central: 2997361
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma</title><author><name sortKey="Carrasquillo, Minerva M" sort="Carrasquillo, Minerva M" uniqKey="Carrasquillo M" first="Minerva M." last="Carrasquillo">Minerva M. Carrasquillo</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Nicholson, Alexandra M" sort="Nicholson, Alexandra M" uniqKey="Nicholson A" first="Alexandra M." last="Nicholson">Alexandra M. Nicholson</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Finch, Nicole" sort="Finch, Nicole" uniqKey="Finch N" first="Nicole" last="Finch">Nicole Finch</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Gibbs, J Raphael" sort="Gibbs, J Raphael" uniqKey="Gibbs J" first="J. Raphael" last="Gibbs">J. Raphael Gibbs</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK</nlm:aff></affiliation></author><author><name sortKey="Baker, Matt" sort="Baker, Matt" uniqKey="Baker M" first="Matt" last="Baker">Matt Baker</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Rutherford, Nicola J" sort="Rutherford, Nicola J" uniqKey="Rutherford N" first="Nicola J." last="Rutherford">Nicola J. Rutherford</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Hunter, Talisha A" sort="Hunter, Talisha A" uniqKey="Hunter T" first="Talisha A." last="Hunter">Talisha A. Hunter</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Dejesus Hernandez, Mariely" sort="Dejesus Hernandez, Mariely" uniqKey="Dejesus Hernandez M" first="Mariely" last="Dejesus-Hernandez">Mariely Dejesus-Hernandez</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Bisceglio, Gina D" sort="Bisceglio, Gina D" uniqKey="Bisceglio G" first="Gina D." last="Bisceglio">Gina D. Bisceglio</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><affiliation><nlm:aff id="aff4">Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Vancouver, British Columbia V5Z 4H4, Canada</nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Crook, Julia E" sort="Crook, Julia E" uniqKey="Crook J" first="Julia E." last="Crook">Julia E. Crook</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Dillman, Allissa" sort="Dillman, Allissa" uniqKey="Dillman A" first="Allissa" last="Dillman">Allissa Dillman</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Hernandez, Dena" sort="Hernandez, Dena" uniqKey="Hernandez D" first="Dena" last="Hernandez">Dena Hernandez</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK</nlm:aff></affiliation></author><author><name sortKey="Petersen, Ronald C" sort="Petersen, Ronald C" uniqKey="Petersen R" first="Ronald C." last="Petersen">Ronald C. Petersen</name><affiliation><nlm:aff id="aff5">Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R." last="Graff-Radford">Neill R. Graff-Radford</name><affiliation><nlm:aff id="aff6">Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Younkin, Steven G" sort="Younkin, Steven G" uniqKey="Younkin S" first="Steven G." last="Younkin">Steven G. Younkin</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21087763</idno><idno type="pmc">2997361</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997361</idno><idno type="RBID">PMC:2997361</idno><idno type="doi">10.1016/j.ajhg.2010.11.002</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000356</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000356</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma</title><author><name sortKey="Carrasquillo, Minerva M" sort="Carrasquillo, Minerva M" uniqKey="Carrasquillo M" first="Minerva M." last="Carrasquillo">Minerva M. Carrasquillo</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Nicholson, Alexandra M" sort="Nicholson, Alexandra M" uniqKey="Nicholson A" first="Alexandra M." last="Nicholson">Alexandra M. Nicholson</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Finch, Nicole" sort="Finch, Nicole" uniqKey="Finch N" first="Nicole" last="Finch">Nicole Finch</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Gibbs, J Raphael" sort="Gibbs, J Raphael" uniqKey="Gibbs J" first="J. Raphael" last="Gibbs">J. Raphael Gibbs</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK</nlm:aff></affiliation></author><author><name sortKey="Baker, Matt" sort="Baker, Matt" uniqKey="Baker M" first="Matt" last="Baker">Matt Baker</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Rutherford, Nicola J" sort="Rutherford, Nicola J" uniqKey="Rutherford N" first="Nicola J." last="Rutherford">Nicola J. Rutherford</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Hunter, Talisha A" sort="Hunter, Talisha A" uniqKey="Hunter T" first="Talisha A." last="Hunter">Talisha A. Hunter</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Dejesus Hernandez, Mariely" sort="Dejesus Hernandez, Mariely" uniqKey="Dejesus Hernandez M" first="Mariely" last="Dejesus-Hernandez">Mariely Dejesus-Hernandez</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Bisceglio, Gina D" sort="Bisceglio, Gina D" uniqKey="Bisceglio G" first="Gina D." last="Bisceglio">Gina D. Bisceglio</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><affiliation><nlm:aff id="aff4">Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Vancouver, British Columbia V5Z 4H4, Canada</nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Crook, Julia E" sort="Crook, Julia E" uniqKey="Crook J" first="Julia E." last="Crook">Julia E. Crook</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Dillman, Allissa" sort="Dillman, Allissa" uniqKey="Dillman A" first="Allissa" last="Dillman">Allissa Dillman</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Hernandez, Dena" sort="Hernandez, Dena" uniqKey="Hernandez D" first="Dena" last="Hernandez">Dena Hernandez</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK</nlm:aff></affiliation></author><author><name sortKey="Petersen, Ronald C" sort="Petersen, Ronald C" uniqKey="Petersen R" first="Ronald C." last="Petersen">Ronald C. Petersen</name><affiliation><nlm:aff id="aff5">Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R." last="Graff-Radford">Neill R. Graff-Radford</name><affiliation><nlm:aff id="aff6">Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Younkin, Steven G" sort="Younkin, Steven G" uniqKey="Younkin S" first="Steven G." last="Younkin">Steven G. Younkin</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><nlm:aff id="aff1">Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (<italic>GRN</italic>) 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 <italic>GRN</italic> mutation status. This study also showed a wide range in plasma GRN levels in non-<italic>GRN</italic> 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<sup>−30</sup>). The association of rs646776 with plasma GRN levels was replicated in two independent series of 508 controls (p = 1.9 × 10<sup>−19</sup>) and 197 FTLD patients (p = 6.4 × 10<sup>−12</sup>). Overall, each copy of the minor C allele decreased GRN levels by ∼15%. SNP rs646776 is located near sortilin (<italic>SORT1)</italic>, and the minor C allele of rs646776 was previously associated with increased <italic>SORT1</italic> 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.</p></div></front></TEI><pmc article-type="brief-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21087763</article-id><article-id pub-id-type="pmc">2997361</article-id><article-id pub-id-type="publisher-id">AJHG791</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2010.11.002</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Carrasquillo</surname><given-names>Minerva M.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">7</xref></contrib><contrib contrib-type="author"><name><surname>Nicholson</surname><given-names>Alexandra M.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">7</xref></contrib><contrib contrib-type="author"><name><surname>Finch</surname><given-names>NiCole</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">7</xref></contrib><contrib contrib-type="author"><name><surname>Gibbs</surname><given-names>J. Raphael</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Baker</surname><given-names>Matt</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rutherford</surname><given-names>Nicola J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hunter</surname><given-names>Talisha A.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>DeJesus-Hernandez</surname><given-names>Mariely</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Bisceglio</surname><given-names>Gina D.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Mackenzie</surname><given-names>Ian R.</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Singleton</surname><given-names>Andrew</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Cookson</surname><given-names>Mark R.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Crook</surname><given-names>Julia E.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Dillman</surname><given-names>Allissa</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Hernandez</surname><given-names>Dena</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Petersen</surname><given-names>Ronald C.</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Graff-Radford</surname><given-names>Neill R.</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Younkin</surname><given-names>Steven G.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rademakers</surname><given-names>Rosa</given-names></name><email>rademakers.rosa@mayo.edu</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</aff><aff id="aff2"><label>2</label>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA</aff><aff id="aff3"><label>3</label>Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK</aff><aff id="aff4"><label>4</label>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Vancouver, British Columbia V5Z 4H4, Canada</aff><aff id="aff5"><label>5</label>Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA</aff><aff id="aff6"><label>6</label>Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>rademakers.rosa@mayo.edu</email></corresp><fn id="fn1"><label>7</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>10</day><month>12</month><year>2010</year></pub-date><volume>87</volume><issue>6</issue><fpage>890</fpage><lpage>897</lpage><history><date date-type="received"><day>7</day><month>10</month><year>2010</year></date><date date-type="rev-recd"><day>4</day><month>11</month><year>2010</year></date><date date-type="accepted"><day>8</day><month>11</month><year>2010</year></date></history><permissions><copyright-statement>© 2010 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2010</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (<italic>GRN</italic>) 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 <italic>GRN</italic> mutation status. This study also showed a wide range in plasma GRN levels in non-<italic>GRN</italic> 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<sup>−30</sup>). The association of rs646776 with plasma GRN levels was replicated in two independent series of 508 controls (p = 1.9 × 10<sup>−19</sup>) and 197 FTLD patients (p = 6.4 × 10<sup>−12</sup>). Overall, each copy of the minor C allele decreased GRN levels by ∼15%. SNP rs646776 is located near sortilin (<italic>SORT1)</italic>, and the minor C allele of rs646776 was previously associated with increased <italic>SORT1</italic> 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.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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