F-box/LRR-repeat protein 7 is genetically associated with Alzheimer’s disease
Identifieur interne : 000730 ( Main/Exploration ); précédent : 000729; suivant : 000731F-box/LRR-repeat protein 7 is genetically associated with Alzheimer’s disease
Auteurs : Giuseppe Tosto [États-Unis] ; Hongjun Fu [États-Unis] ; Badri N. Vardarajan [États-Unis] ; Joseph H. Lee [États-Unis] ; Rong Cheng [États-Unis] ; Dolly Reyes-Dumeyer [États-Unis] ; Rafael Lantigua [États-Unis] ; Martin Medrano [République dominicaine] ; Ivonne Z. Jimenez-Velazquez [Porto Rico] ; Mitchell S V. Elkind [États-Unis] ; Clinton B. Wright ; Ralph L. Sacco ; Margaret Pericak-Vance ; Lindsay Farrer [États-Unis] ; Ekaterina Rogaeva ; Peter St George-Hyslop [Royaume-Uni] ; Christiane Reitz [États-Unis] ; Richard Mayeux [États-Unis]Source :
- Annals of Clinical and Translational Neurology [ 2328-9503 ] ; 2015.
Abstract
In the context of late-onset Alzheimer’s disease (LOAD) over 20 genes have been identified but, aside
About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (
A novel locus, rs75002042 in
FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
Url:
DOI: 10.1002/acn3.223
PubMed: 26339675
PubMed Central: 4554442
Affiliations:
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Le document en format XML
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Vardarajan</name><affiliation wicri:level="2"><nlm:aff id="au1"><institution>The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au2"><institution>The Gertrude H. Sergievsky Center, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation></author><author><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H" last="Lee">Joseph H. Lee</name><affiliation wicri:level="2"><nlm:aff id="au1"><institution>The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au2"><institution>The Gertrude H. 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Sergievsky Center, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation></author><author><name sortKey="Lantigua, Rafael" sort="Lantigua, Rafael" uniqKey="Lantigua R" first="Rafael" last="Lantigua">Rafael Lantigua</name><affiliation wicri:level="2"><nlm:aff id="au3"><institution>Department of Medicine College of Physicians and Surgeons, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation></author><author><name sortKey="Medrano, Martin" sort="Medrano, Martin" uniqKey="Medrano M" first="Martin" last="Medrano">Martin Medrano</name><affiliation wicri:level="1"><nlm:aff id="au4"><institution>School of Medicine, Pontificia Universidad Catolica Madre y Maestra</institution><addr-line>Santiago, Dominican Republic</addr-line></nlm:aff><country xml:lang="fr">République dominicaine</country><wicri:regionArea>Santiago</wicri:regionArea></affiliation></author><author><name sortKey="Jimenez Velazquez, Ivonne Z" sort="Jimenez Velazquez, Ivonne Z" uniqKey="Jimenez Velazquez I" first="Ivonne Z" last="Jimenez-Velazquez">Ivonne Z. Jimenez-Velazquez</name><affiliation wicri:level="1"><nlm:aff id="au5"><institution>Department of Medicine, Geriatrics Program, School of Medicine, University of Puerto Rico</institution><addr-line>San Juan, Puerto Rico</addr-line></nlm:aff><country xml:lang="fr">Porto Rico</country><wicri:regionArea>San Juan</wicri:regionArea></affiliation></author><author><name sortKey="Elkind, Mitchell S V" sort="Elkind, Mitchell S V" uniqKey="Elkind M" first="Mitchell S V" last="Elkind">Mitchell S V. Elkind</name><affiliation wicri:level="2"><nlm:aff id="au2"><institution>The Gertrude H. Sergievsky Center, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Neurology, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation></author><author><name sortKey="Wright, Clinton B" sort="Wright, Clinton B" uniqKey="Wright C" first="Clinton B" last="Wright">Clinton B. Wright</name><affiliation><nlm:aff id="au7"><institution>Evelyn F. McKnight Brain Institute and Departments of Neurology, Public Health Sciences, John T. McDonald Department of Human Genetics, University of Miami</institution><addr-line>Miami, Florida, 33136</addr-line></nlm:aff><wicri:noCountry code="subfield">33136</wicri:noCountry></affiliation></author><author><name sortKey="Sacco, Ralph L" sort="Sacco, Ralph L" uniqKey="Sacco R" first="Ralph L" last="Sacco">Ralph L. Sacco</name><affiliation><nlm:aff id="au7"><institution>Evelyn F. McKnight Brain Institute and Departments of Neurology, Public Health Sciences, John T. McDonald Department of Human Genetics, University of Miami</institution><addr-line>Miami, Florida, 33136</addr-line></nlm:aff><wicri:noCountry code="subfield">33136</wicri:noCountry></affiliation><affiliation><nlm:aff id="au8"><institution>Neuroscience Program, Leonard M. Miller School of Medicine, University of Miami</institution><addr-line>Miami, Florida, 33136</addr-line></nlm:aff><wicri:noCountry code="subfield">33136</wicri:noCountry></affiliation></author><author><name sortKey="Pericak Vance, Margaret" sort="Pericak Vance, Margaret" uniqKey="Pericak Vance M" first="Margaret" last="Pericak-Vance">Margaret Pericak-Vance</name><affiliation><nlm:aff id="au8"><institution>Neuroscience Program, Leonard M. Miller School of Medicine, University of Miami</institution><addr-line>Miami, Florida, 33136</addr-line></nlm:aff><wicri:noCountry code="subfield">33136</wicri:noCountry></affiliation><affiliation><nlm:aff id="au9"><institution>The John P. Hussman Institute for Human Genomics, University of Miami</institution><addr-line>Miami, Florida, 33136</addr-line></nlm:aff><wicri:noCountry code="subfield">33136</wicri:noCountry></affiliation></author><author><name sortKey="Farrer, Lindsay" sort="Farrer, Lindsay" uniqKey="Farrer L" first="Lindsay" last="Farrer">Lindsay Farrer</name><affiliation wicri:level="2"><nlm:aff id="au10"><institution>Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics and Epidemiology, Boston University Schools of Medicine and Public Health</institution><addr-line>Boston, Massachusetts</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Boston</wicri:cityArea></affiliation></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><affiliation><nlm:aff id="au11"><institution>Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto</institution><addr-line>Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</addr-line></nlm:aff><wicri:noCountry code="subfield">M5T 2S8</wicri:noCountry></affiliation></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name><affiliation><nlm:aff id="au11"><institution>Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto</institution><addr-line>Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</addr-line></nlm:aff><wicri:noCountry code="subfield">M5T 2S8</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="au12"><institution>Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge</institution><addr-line>Cambridge, CB2 0XY, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cambridge, CB2 0XY</wicri:regionArea><wicri:noRegion>CB2 0XY</wicri:noRegion></affiliation></author><author><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name><affiliation wicri:level="2"><nlm:aff id="au1"><institution>The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au2"><institution>The Gertrude H. Sergievsky Center, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Neurology, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation></author><author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><affiliation wicri:level="2"><nlm:aff id="au1"><institution>The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au2"><institution>The Gertrude H. Sergievsky Center, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Neurology, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au13"><institution>Department of Psychiatry, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="au14"><institution>Department of Epidemiology, School of Public Health, Columbia University</institution><addr-line>New York, New York</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York</wicri:cityArea></affiliation></author></analytic><series><title level="j">Annals of Clinical and Translational Neurology</title><idno type="ISSN">2328-9503</idno><idno type="eISSN">2328-9503</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective</title><p>In the context of late-onset Alzheimer’s disease (LOAD) over 20 genes have been identified but, aside <italic>APOE</italic>, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.</p></sec><sec><title>Methods</title><p>About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (<italic>n</italic> = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.</p></sec><sec><title>Results</title><p>A novel locus, rs75002042 in <italic>FBXL7</italic> (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, <italic>P</italic> = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, <italic>P</italic> = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < <italic>P</italic> < 0.02) used for replication.</p></sec><sec><title>Interpretation</title><p>FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Thies, W" uniqKey="Thies W">W Thies</name></author><author><name sortKey="Bleiler, L" uniqKey="Bleiler L">L Bleiler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Slooter, Aj" uniqKey="Slooter A">AJ Slooter</name></author><author><name sortKey="Cruts, M" uniqKey="Cruts M">M Cruts</name></author><author><name sortKey="Kalmijn, S" uniqKey="Kalmijn S">S Kalmijn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lambert, J C" uniqKey="Lambert J">J-C Lambert</name></author><author><name sortKey="Heath, S" uniqKey="Heath S">S Heath</name></author><author><name sortKey="Even, G" uniqKey="Even G">G Even</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harold, D" uniqKey="Harold D">D 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Jewett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lin, P I" uniqKey="Lin P">P-I Lin</name></author><author><name sortKey="Vance, Jm" uniqKey="Vance J">JM Vance</name></author><author><name sortKey="Pericak Vance, Ma" uniqKey="Pericak Vance M">MA Pericak-Vance</name></author><author><name sortKey="Martin, Er" uniqKey="Martin E">ER Martin</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Porto Rico</li><li>Royaume-Uni</li><li>République dominicaine</li><li>États-Unis</li></country><region><li>Massachusetts</li><li>État de New York</li></region></list><tree><noCountry><name sortKey="Pericak Vance, Margaret" sort="Pericak Vance, Margaret" uniqKey="Pericak Vance M" first="Margaret" last="Pericak-Vance">Margaret Pericak-Vance</name><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><name sortKey="Sacco, Ralph L" sort="Sacco, Ralph L" uniqKey="Sacco R" first="Ralph L" last="Sacco">Ralph L. Sacco</name><name sortKey="Wright, Clinton B" sort="Wright, Clinton B" uniqKey="Wright C" first="Clinton B" last="Wright">Clinton B. Wright</name></noCountry><country name="États-Unis"><region name="État de New York"><name sortKey="Tosto, Giuseppe" sort="Tosto, Giuseppe" uniqKey="Tosto G" first="Giuseppe" last="Tosto">Giuseppe Tosto</name></region><name sortKey="Cheng, Rong" sort="Cheng, Rong" uniqKey="Cheng R" first="Rong" last="Cheng">Rong Cheng</name><name sortKey="Cheng, Rong" sort="Cheng, Rong" uniqKey="Cheng R" first="Rong" last="Cheng">Rong Cheng</name><name sortKey="Elkind, Mitchell S V" sort="Elkind, Mitchell S V" uniqKey="Elkind M" first="Mitchell S V" last="Elkind">Mitchell S V. Elkind</name><name sortKey="Elkind, Mitchell S V" sort="Elkind, Mitchell S V" uniqKey="Elkind M" first="Mitchell S V" last="Elkind">Mitchell S V. Elkind</name><name sortKey="Farrer, Lindsay" sort="Farrer, Lindsay" uniqKey="Farrer L" first="Lindsay" last="Farrer">Lindsay Farrer</name><name sortKey="Fu, Hongjun" sort="Fu, Hongjun" uniqKey="Fu H" first="Hongjun" last="Fu">Hongjun Fu</name><name sortKey="Lantigua, Rafael" sort="Lantigua, Rafael" uniqKey="Lantigua R" first="Rafael" last="Lantigua">Rafael Lantigua</name><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H" last="Lee">Joseph H. Lee</name><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H" last="Lee">Joseph H. Lee</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name><name sortKey="Reyes Dumeyer, Dolly" sort="Reyes Dumeyer, Dolly" uniqKey="Reyes Dumeyer D" first="Dolly" last="Reyes-Dumeyer">Dolly Reyes-Dumeyer</name><name sortKey="Reyes Dumeyer, Dolly" sort="Reyes Dumeyer, Dolly" uniqKey="Reyes Dumeyer D" first="Dolly" last="Reyes-Dumeyer">Dolly Reyes-Dumeyer</name><name sortKey="Tosto, Giuseppe" sort="Tosto, Giuseppe" uniqKey="Tosto G" first="Giuseppe" last="Tosto">Giuseppe Tosto</name><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N" last="Vardarajan">Badri N. Vardarajan</name><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N" last="Vardarajan">Badri N. Vardarajan</name></country><country name="République dominicaine"><noRegion><name sortKey="Medrano, Martin" sort="Medrano, Martin" uniqKey="Medrano M" first="Martin" last="Medrano">Martin Medrano</name></noRegion></country><country name="Porto Rico"><noRegion><name sortKey="Jimenez Velazquez, Ivonne Z" sort="Jimenez Velazquez, Ivonne Z" uniqKey="Jimenez Velazquez I" first="Ivonne Z" last="Jimenez-Velazquez">Ivonne Z. Jimenez-Velazquez</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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