Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
Identifieur interne : 009834 ( Main/Exploration ); précédent : 009833; suivant : 009835Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
Auteurs : Jian-Liang Li [États-Unis] ; Michael R. Hayden [Canada] ; Simon C. Warby [Canada] ; Alexandra Durr [France] ; Patrick J. Morrison [Royaume-Uni] ; Martha Nance [États-Unis] ; Christopher A. Ross [États-Unis] ; Russell L. Margolis [États-Unis] ; Adam Rosenblatt [États-Unis] ; Ferdinando Squitieri [Italie] ; Luigi Frati [Italie] ; Estrella G Mez-Tortosa [Espagne] ; Carmen Ayuso García [Espagne] ; Oksana Suchowersky [Canada] ; Mary Lou Klimek [Canada] ; Ronald Ja Trent [Australie] ; Elizabeth Mccusker [Australie] ; Andrea Novelletto [Italie] ; Marina Frontali [Italie] ; Jane S. Paulsen [États-Unis] ; Randi Jones [États-Unis] ; Tetsuo Ashizawa [États-Unis] ; Alice Lazzarini [États-Unis] ; Vanessa C. Wheeler [États-Unis] ; Ranjana Prakash [États-Unis] ; Gang Xu [États-Unis] ; Luc Djoussé [États-Unis] ; Jayalakshmi Srinidhi Mysore [États-Unis] ; Tammy Gillis [États-Unis] ; Michael Hakky [États-Unis] ; L Adrienne Cupples [États-Unis] ; Marie H. Saint-Hilaire [États-Unis] ; Jang-Ho J. Cha [États-Unis] ; Steven M. Hersch [États-Unis] ; John B. Penney [États-Unis] ; Madaline B. Harrison [États-Unis] ; Susan L. Perlman [États-Unis] ; Andrea Zanko [États-Unis] ; Ruth K. Abramson [États-Unis] ; Anthony J. Lechich [États-Unis] ; Ayana Duckett [États-Unis] ; Karen Marder [États-Unis] ; P Michael Conneally [États-Unis] ; James F. Gusella [États-Unis] ; Marcy E. Macdonald [États-Unis] ; Richard H. Myers [États-Unis]Source :
- BMC Medical Genetics [ 1471-2350 ] ; 2006.
Abstract
Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the
In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.
Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87,
In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.
Url:
DOI: 10.1186/1471-2350-7-71
PubMed: 16914060
PubMed Central: 1586197
Affiliations:
- Australie, Canada, Espagne, France, Italie, Royaume-Uni, États-Unis
- Alberta, Californie, Caroline du Sud, Communauté de Madrid, Géorgie (États-Unis), Indiana, Iowa, Latium, Maryland, Massachusetts, Minnesota, New Jersey, Nouvelle-Galles du Sud, Texas, Virginie, État de New York, Île-de-France
- Calgary, Iowa City, Madrid, Paris, Rome, Sydney
- Université de Calgary, Université de Sydney, Université de l'Iowa
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Trent</name><affiliation wicri:level="4"><nlm:aff id="I16">Department of Medicine, University of Sydney, Sydney, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Medicine, University of Sydney, Sydney</wicri:regionArea><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><author><name sortKey="Mccusker, Elizabeth" sort="Mccusker, Elizabeth" uniqKey="Mccusker E" first="Elizabeth" last="Mccusker">Elizabeth Mccusker</name><affiliation wicri:level="3"><nlm:aff id="I17">Neurology Department, Westmead Hospital, Sydney, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Neurology Department, Westmead Hospital, Sydney</wicri:regionArea><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du 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type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Paulsen, Jane S" sort="Paulsen, Jane S" uniqKey="Paulsen J" first="Jane S" last="Paulsen">Jane S. Paulsen</name><affiliation wicri:level="4"><nlm:aff id="I20">Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa, Iowa City, Iowa</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Jones, Randi" sort="Jones, Randi" uniqKey="Jones R" first="Randi" last="Jones">Randi Jones</name><affiliation wicri:level="2"><nlm:aff id="I21">Neurology Department, Emory University, Atlanta, Georgia, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Neurology Department, Emory University, Atlanta, Georgia</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Ashizawa, Tetsuo" sort="Ashizawa, Tetsuo" uniqKey="Ashizawa T" first="Tetsuo" last="Ashizawa">Tetsuo Ashizawa</name><affiliation wicri:level="2"><nlm:aff id="I22">Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of Texas Medical Branch, Galveston, TX</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Lazzarini, Alice" sort="Lazzarini, Alice" uniqKey="Lazzarini A" first="Alice" last="Lazzarini">Alice Lazzarini</name><affiliation wicri:level="1"><nlm:aff id="I23">Department of Neurology, Robert Wood Johnson school of Medicine and Dentistry of New Jersey, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Robert Wood Johnson school of Medicine and Dentistry of New Jersey</wicri:regionArea><wicri:noRegion>Robert Wood Johnson school of Medicine and Dentistry of New Jersey</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="I24">Novartis Pharmaceuticals, New Brunswick, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals, New Brunswick, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Wheeler, Vanessa C" sort="Wheeler, Vanessa C" uniqKey="Wheeler V" first="Vanessa C" last="Wheeler">Vanessa C. Wheeler</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Prakash, Ranjana" sort="Prakash, Ranjana" uniqKey="Prakash R" first="Ranjana" last="Prakash">Ranjana Prakash</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Xu, Gang" sort="Xu, Gang" uniqKey="Xu G" first="Gang" last="Xu">Gang Xu</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I2">Bioinformatics Program, Boston University, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics Program, Boston University, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Djousse, Luc" sort="Djousse, Luc" uniqKey="Djousse L" first="Luc" last="Djoussé">Luc Djoussé</name><affiliation wicri:level="2"><nlm:aff id="I26">Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Mysore, Jayalakshmi Srinidhi" sort="Mysore, Jayalakshmi Srinidhi" uniqKey="Mysore J" first="Jayalakshmi Srinidhi" last="Mysore">Jayalakshmi Srinidhi Mysore</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Gillis, Tammy" sort="Gillis, Tammy" uniqKey="Gillis T" first="Tammy" last="Gillis">Tammy Gillis</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Hakky, Michael" sort="Hakky, Michael" uniqKey="Hakky M" first="Michael" last="Hakky">Michael Hakky</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Cupples, L Adrienne" sort="Cupples, L Adrienne" uniqKey="Cupples L" first="L Adrienne" last="Cupples">L Adrienne Cupples</name><affiliation wicri:level="1"><nlm:aff id="I27">Department of Biostatistics, School of Public Health, Boston University, Boston MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biostatistics, School of Public Health, Boston University, Boston MA</wicri:regionArea><wicri:noRegion>Boston MA</wicri:noRegion></affiliation></author><author><name sortKey="Saint Hilaire, Marie H" sort="Saint Hilaire, Marie H" uniqKey="Saint Hilaire M" first="Marie H" last="Saint-Hilaire">Marie H. Saint-Hilaire</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Cha, Jang Ho J" sort="Cha, Jang Ho J" uniqKey="Cha J" first="Jang-Ho J" last="Cha">Jang-Ho J. Cha</name><affiliation wicri:level="2"><nlm:aff id="I28">Department of Neurology, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Hersch, Steven M" sort="Hersch, Steven M" uniqKey="Hersch S" first="Steven M" last="Hersch">Steven M. Hersch</name><affiliation wicri:level="2"><nlm:aff id="I28">Department of Neurology, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Penney, John B" sort="Penney, John B" uniqKey="Penney J" first="John B" last="Penney">John B. Penney</name><affiliation wicri:level="2"><nlm:aff id="I28">Department of Neurology, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Harrison, Madaline B" sort="Harrison, Madaline B" uniqKey="Harrison M" first="Madaline B" last="Harrison">Madaline B. Harrison</name><affiliation wicri:level="2"><nlm:aff id="I29">Health Sciences Center, University of Virginia, Charlottesville, Virginia, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Health Sciences Center, University of Virginia, Charlottesville, Virginia</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Perlman, Susan L" sort="Perlman, Susan L" uniqKey="Perlman S" first="Susan L" last="Perlman">Susan L. Perlman</name><affiliation wicri:level="2"><nlm:aff id="I30">Department of Neurology, University of California at Los Angeles, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of California at Los Angeles, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Zanko, Andrea" sort="Zanko, Andrea" uniqKey="Zanko A" first="Andrea" last="Zanko">Andrea Zanko</name><affiliation wicri:level="2"><nlm:aff id="I31">Division of Medical Genetics, UCSF, San Francisco, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Medical Genetics, UCSF, San Francisco, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Abramson, Ruth K" sort="Abramson, Ruth K" uniqKey="Abramson R" first="Ruth K" last="Abramson">Ruth K. Abramson</name><affiliation wicri:level="2"><nlm:aff id="I32">WMS Hall Psychiatric Institute, Columbia, South Carolina, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>WMS Hall Psychiatric Institute, Columbia, South Carolina</wicri:regionArea><placeName><region type="state">Caroline du Sud</region></placeName></affiliation></author><author><name sortKey="Lechich, Anthony J" sort="Lechich, Anthony J" uniqKey="Lechich A" first="Anthony J" last="Lechich">Anthony J. Lechich</name><affiliation wicri:level="2"><nlm:aff id="I33">Department of Neurology, Columbia College of Physicians, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia College of Physicians, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Duckett, Ayana" sort="Duckett, Ayana" uniqKey="Duckett A" first="Ayana" last="Duckett">Ayana Duckett</name><affiliation wicri:level="2"><nlm:aff id="I33">Department of Neurology, Columbia College of Physicians, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia College of Physicians, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name><affiliation wicri:level="2"><nlm:aff id="I33">Department of Neurology, Columbia College of Physicians, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia College of Physicians, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Conneally, P Michael" sort="Conneally, P Michael" uniqKey="Conneally P" first="P Michael" last="Conneally">P Michael Conneally</name><affiliation wicri:level="2"><nlm:aff id="I34">Department of Genetics, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, Indiana University School of Medicine, Indianapolis, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Gusella, James F" sort="Gusella, James F" uniqKey="Gusella J" first="James F" last="Gusella">James F. Gusella</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I35">Department of Genetics, Harvard Medical School, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, Harvard Medical School, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Macdonald, Marcy E" sort="Macdonald, Marcy E" uniqKey="Macdonald M" first="Marcy E" last="Macdonald">Marcy E. Macdonald</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Myers, Richard H" sort="Myers, Richard H" uniqKey="Myers R" first="Richard H" last="Myers">Richard H. Myers</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I2">Bioinformatics Program, Boston University, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics Program, Boston University, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">16914060</idno><idno type="pmc">1586197</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586197</idno><idno type="RBID">PMC:1586197</idno><idno type="doi">10.1186/1471-2350-7-71</idno><date when="2006">2006</date><idno type="wicri:Area/Pmc/Corpus">001098</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001098</idno><idno type="wicri:Area/Pmc/Curation">000F59</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000F59</idno><idno type="wicri:Area/Pmc/Checkpoint">002C08</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">002C08</idno><idno type="wicri:Area/Ncbi/Merge">000210</idno><idno type="wicri:Area/Ncbi/Curation">000210</idno><idno type="wicri:Area/Ncbi/Checkpoint">000210</idno><idno type="wicri:Area/Main/Merge">00A291</idno><idno type="wicri:Area/Main/Curation">009834</idno><idno type="wicri:Area/Main/Exploration">009834</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study</title><author><name sortKey="Li, Jian Liang" sort="Li, Jian Liang" uniqKey="Li J" first="Jian-Liang" last="Li">Jian-Liang Li</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I2">Bioinformatics Program, Boston University, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics Program, Boston University, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I3">Department of Biological Technologies, Wyeth Research, Cambridge, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Technologies, Wyeth Research, Cambridge, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Hayden, Michael R" sort="Hayden, Michael R" uniqKey="Hayden M" first="Michael R" last="Hayden">Michael R. Hayden</name><affiliation wicri:level="1"><nlm:aff id="I4">Centre for Molecular Medicine & Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Molecular Medicine & Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Warby, Simon C" sort="Warby, Simon C" uniqKey="Warby S" first="Simon C" last="Warby">Simon C. Warby</name><affiliation wicri:level="1"><nlm:aff id="I4">Centre for Molecular Medicine & Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Molecular Medicine & Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Durr, Alexandra" sort="Durr, Alexandra" uniqKey="Durr A" first="Alexandra" last="Durr">Alexandra Durr</name><affiliation wicri:level="3"><nlm:aff id="I5">INSERM U679, Hôpital de la Salpêtrière, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM U679, Hôpital de la Salpêtrière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Morrison, Patrick J" sort="Morrison, Patrick J" uniqKey="Morrison P" first="Patrick J" last="Morrison">Patrick J. Morrison</name><affiliation wicri:level="1"><nlm:aff id="I6">Department of Medical Genetics, Belfast City Hospital, Belfast, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical Genetics, Belfast City Hospital, Belfast</wicri:regionArea><wicri:noRegion>Belfast</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="I7">School of Biomedical Science, University of Ulster, Coleraine, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Biomedical Science, University of Ulster, Coleraine</wicri:regionArea><wicri:noRegion>Coleraine</wicri:noRegion></affiliation></author><author><name sortKey="Nance, Martha" sort="Nance, Martha" uniqKey="Nance M" first="Martha" last="Nance">Martha Nance</name><affiliation wicri:level="2"><nlm:aff id="I8">Department of Neurology, Hennepin County Medical Center, Minneapolis, Minnesota, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Hennepin County Medical Center, Minneapolis, Minnesota</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A" last="Ross">Christopher A. Ross</name><affiliation wicri:level="2"><nlm:aff id="I9">Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I10">Program in Cellular and Molecular Medicine, John Hopkins University, Baltimore, Maryland, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Cellular and Molecular Medicine, John Hopkins University, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I11">Department of Neuroscience, John Hopkins University, Baltimore, Maryland, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, John Hopkins University, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Margolis, Russell L" sort="Margolis, Russell L" uniqKey="Margolis R" first="Russell L" last="Margolis">Russell L. Margolis</name><affiliation wicri:level="2"><nlm:aff id="I9">Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I10">Program in Cellular and Molecular Medicine, John Hopkins University, Baltimore, Maryland, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Cellular and Molecular Medicine, John Hopkins University, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Rosenblatt, Adam" sort="Rosenblatt, Adam" uniqKey="Rosenblatt A" first="Adam" last="Rosenblatt">Adam Rosenblatt</name><affiliation wicri:level="2"><nlm:aff id="I9">Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Squitieri, Ferdinando" sort="Squitieri, Ferdinando" uniqKey="Squitieri F" first="Ferdinando" last="Squitieri">Ferdinando Squitieri</name><affiliation wicri:level="1"><nlm:aff id="I12">Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Neurogenetics Unit, IRCCS Neuromed, Pozzilli</wicri:regionArea><wicri:noRegion>Pozzilli</wicri:noRegion></affiliation></author><author><name sortKey="Frati, Luigi" sort="Frati, Luigi" uniqKey="Frati L" first="Luigi" last="Frati">Luigi Frati</name><affiliation wicri:level="3"><nlm:aff id="I13">Dept of Experimental Medicine and Pathology, University "La Sapienza" of Rome, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Dept of Experimental Medicine and Pathology, University "La Sapienza" of Rome, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="G Mez Tortosa, Estrella" sort="G Mez Tortosa, Estrella" uniqKey="G Mez Tortosa E" first="Estrella" last="G Mez-Tortosa">Estrella G Mez-Tortosa</name><affiliation wicri:level="3"><nlm:aff id="I14">Servicio de Neurología y Genética, Fundación Jiménez Díaz, Madrid, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Servicio de Neurología y Genética, Fundación Jiménez Díaz, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Garcia, Carmen Ayuso" sort="Garcia, Carmen Ayuso" uniqKey="Garcia C" first="Carmen Ayuso" last="García">Carmen Ayuso García</name><affiliation wicri:level="3"><nlm:aff id="I14">Servicio de Neurología y Genética, Fundación Jiménez Díaz, Madrid, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Servicio de Neurología y Genética, Fundación Jiménez Díaz, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Suchowersky, Oksana" sort="Suchowersky, Oksana" uniqKey="Suchowersky O" first="Oksana" last="Suchowersky">Oksana Suchowersky</name><affiliation wicri:level="4"><nlm:aff id="I15">Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta</wicri:regionArea><orgName type="university">Université de Calgary</orgName><placeName><settlement type="city">Calgary</settlement><region type="state">Alberta</region></placeName></affiliation></author><author><name sortKey="Klimek, Mary Lou" sort="Klimek, Mary Lou" uniqKey="Klimek M" first="Mary Lou" last="Klimek">Mary Lou Klimek</name><affiliation wicri:level="4"><nlm:aff id="I15">Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta</wicri:regionArea><orgName type="university">Université de Calgary</orgName><placeName><settlement type="city">Calgary</settlement><region type="state">Alberta</region></placeName></affiliation></author><author><name sortKey="Trent, Ronald Ja" sort="Trent, Ronald Ja" uniqKey="Trent R" first="Ronald Ja" last="Trent">Ronald Ja Trent</name><affiliation wicri:level="4"><nlm:aff id="I16">Department of Medicine, University of Sydney, Sydney, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Medicine, University of Sydney, Sydney</wicri:regionArea><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><author><name sortKey="Mccusker, Elizabeth" sort="Mccusker, Elizabeth" uniqKey="Mccusker E" first="Elizabeth" last="Mccusker">Elizabeth Mccusker</name><affiliation wicri:level="3"><nlm:aff id="I17">Neurology Department, Westmead Hospital, Sydney, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Neurology Department, Westmead Hospital, Sydney</wicri:regionArea><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Novelletto, Andrea" sort="Novelletto, Andrea" uniqKey="Novelletto A" first="Andrea" last="Novelletto">Andrea Novelletto</name><affiliation wicri:level="1"><nlm:aff id="I18">Department of Biology, University "Tor Vergata", 00133 Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biology, University "Tor Vergata", 00133 Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Frontali, Marina" sort="Frontali, Marina" uniqKey="Frontali M" first="Marina" last="Frontali">Marina Frontali</name><affiliation wicri:level="3"><nlm:aff id="I19">Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Institute of Neurobiology and Molecular Medicine, CNR, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Paulsen, Jane S" sort="Paulsen, Jane S" uniqKey="Paulsen J" first="Jane S" last="Paulsen">Jane S. Paulsen</name><affiliation wicri:level="4"><nlm:aff id="I20">Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa, Iowa City, Iowa</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Jones, Randi" sort="Jones, Randi" uniqKey="Jones R" first="Randi" last="Jones">Randi Jones</name><affiliation wicri:level="2"><nlm:aff id="I21">Neurology Department, Emory University, Atlanta, Georgia, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Neurology Department, Emory University, Atlanta, Georgia</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Ashizawa, Tetsuo" sort="Ashizawa, Tetsuo" uniqKey="Ashizawa T" first="Tetsuo" last="Ashizawa">Tetsuo Ashizawa</name><affiliation wicri:level="2"><nlm:aff id="I22">Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of Texas Medical Branch, Galveston, TX</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Lazzarini, Alice" sort="Lazzarini, Alice" uniqKey="Lazzarini A" first="Alice" last="Lazzarini">Alice Lazzarini</name><affiliation wicri:level="1"><nlm:aff id="I23">Department of Neurology, Robert Wood Johnson school of Medicine and Dentistry of New Jersey, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Robert Wood Johnson school of Medicine and Dentistry of New Jersey</wicri:regionArea><wicri:noRegion>Robert Wood Johnson school of Medicine and Dentistry of New Jersey</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="I24">Novartis Pharmaceuticals, New Brunswick, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals, New Brunswick, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Wheeler, Vanessa C" sort="Wheeler, Vanessa C" uniqKey="Wheeler V" first="Vanessa C" last="Wheeler">Vanessa C. Wheeler</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Prakash, Ranjana" sort="Prakash, Ranjana" uniqKey="Prakash R" first="Ranjana" last="Prakash">Ranjana Prakash</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Xu, Gang" sort="Xu, Gang" uniqKey="Xu G" first="Gang" last="Xu">Gang Xu</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I2">Bioinformatics Program, Boston University, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics Program, Boston University, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Djousse, Luc" sort="Djousse, Luc" uniqKey="Djousse L" first="Luc" last="Djoussé">Luc Djoussé</name><affiliation wicri:level="2"><nlm:aff id="I26">Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Mysore, Jayalakshmi Srinidhi" sort="Mysore, Jayalakshmi Srinidhi" uniqKey="Mysore J" first="Jayalakshmi Srinidhi" last="Mysore">Jayalakshmi Srinidhi Mysore</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Gillis, Tammy" sort="Gillis, Tammy" uniqKey="Gillis T" first="Tammy" last="Gillis">Tammy Gillis</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Hakky, Michael" sort="Hakky, Michael" uniqKey="Hakky M" first="Michael" last="Hakky">Michael Hakky</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Cupples, L Adrienne" sort="Cupples, L Adrienne" uniqKey="Cupples L" first="L Adrienne" last="Cupples">L Adrienne Cupples</name><affiliation wicri:level="1"><nlm:aff id="I27">Department of Biostatistics, School of Public Health, Boston University, Boston MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biostatistics, School of Public Health, Boston University, Boston MA</wicri:regionArea><wicri:noRegion>Boston MA</wicri:noRegion></affiliation></author><author><name sortKey="Saint Hilaire, Marie H" sort="Saint Hilaire, Marie H" uniqKey="Saint Hilaire M" first="Marie H" last="Saint-Hilaire">Marie H. Saint-Hilaire</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Cha, Jang Ho J" sort="Cha, Jang Ho J" uniqKey="Cha J" first="Jang-Ho J" last="Cha">Jang-Ho J. Cha</name><affiliation wicri:level="2"><nlm:aff id="I28">Department of Neurology, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Hersch, Steven M" sort="Hersch, Steven M" uniqKey="Hersch S" first="Steven M" last="Hersch">Steven M. Hersch</name><affiliation wicri:level="2"><nlm:aff id="I28">Department of Neurology, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Penney, John B" sort="Penney, John B" uniqKey="Penney J" first="John B" last="Penney">John B. Penney</name><affiliation wicri:level="2"><nlm:aff id="I28">Department of Neurology, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Harrison, Madaline B" sort="Harrison, Madaline B" uniqKey="Harrison M" first="Madaline B" last="Harrison">Madaline B. Harrison</name><affiliation wicri:level="2"><nlm:aff id="I29">Health Sciences Center, University of Virginia, Charlottesville, Virginia, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Health Sciences Center, University of Virginia, Charlottesville, Virginia</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Perlman, Susan L" sort="Perlman, Susan L" uniqKey="Perlman S" first="Susan L" last="Perlman">Susan L. Perlman</name><affiliation wicri:level="2"><nlm:aff id="I30">Department of Neurology, University of California at Los Angeles, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of California at Los Angeles, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Zanko, Andrea" sort="Zanko, Andrea" uniqKey="Zanko A" first="Andrea" last="Zanko">Andrea Zanko</name><affiliation wicri:level="2"><nlm:aff id="I31">Division of Medical Genetics, UCSF, San Francisco, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Medical Genetics, UCSF, San Francisco, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Abramson, Ruth K" sort="Abramson, Ruth K" uniqKey="Abramson R" first="Ruth K" last="Abramson">Ruth K. Abramson</name><affiliation wicri:level="2"><nlm:aff id="I32">WMS Hall Psychiatric Institute, Columbia, South Carolina, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>WMS Hall Psychiatric Institute, Columbia, South Carolina</wicri:regionArea><placeName><region type="state">Caroline du Sud</region></placeName></affiliation></author><author><name sortKey="Lechich, Anthony J" sort="Lechich, Anthony J" uniqKey="Lechich A" first="Anthony J" last="Lechich">Anthony J. Lechich</name><affiliation wicri:level="2"><nlm:aff id="I33">Department of Neurology, Columbia College of Physicians, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia College of Physicians, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Duckett, Ayana" sort="Duckett, Ayana" uniqKey="Duckett A" first="Ayana" last="Duckett">Ayana Duckett</name><affiliation wicri:level="2"><nlm:aff id="I33">Department of Neurology, Columbia College of Physicians, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia College of Physicians, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name><affiliation wicri:level="2"><nlm:aff id="I33">Department of Neurology, Columbia College of Physicians, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia College of Physicians, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Conneally, P Michael" sort="Conneally, P Michael" uniqKey="Conneally P" first="P Michael" last="Conneally">P Michael Conneally</name><affiliation wicri:level="2"><nlm:aff id="I34">Department of Genetics, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, Indiana University School of Medicine, Indianapolis, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Gusella, James F" sort="Gusella, James F" uniqKey="Gusella J" first="James F" last="Gusella">James F. Gusella</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I35">Department of Genetics, Harvard Medical School, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, Harvard Medical School, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Macdonald, Marcy E" sort="Macdonald, Marcy E" uniqKey="Macdonald M" first="Marcy E" last="Macdonald">Marcy E. Macdonald</name><affiliation wicri:level="2"><nlm:aff id="I25">Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Myers, Richard H" sort="Myers, Richard H" uniqKey="Myers R" first="Richard H" last="Myers">Richard H. Myers</name><affiliation wicri:level="2"><nlm:aff id="I1">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Boston University School of Medicine, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="I2">Bioinformatics Program, Boston University, Boston, MA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics Program, Boston University, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author></analytic><series><title level="j">BMC Medical Genetics</title><idno type="eISSN">1471-2350</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the <italic>HD </italic>gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.</p></sec><sec sec-type="methods"><title>Methods</title><p>In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.</p></sec><sec><title>Results</title><p>Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, <italic>p </italic>= 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, <italic>p </italic>= 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, <italic>p </italic>= 0.03) and the combined sample (LOD = 1.78, <italic>p </italic>= 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.</p></sec><sec><title>Conclusion</title><p>In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>Canada</li><li>Espagne</li><li>France</li><li>Italie</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Alberta</li><li>Californie</li><li>Caroline du Sud</li><li>Communauté de Madrid</li><li>Géorgie (États-Unis)</li><li>Indiana</li><li>Iowa</li><li>Latium</li><li>Maryland</li><li>Massachusetts</li><li>Minnesota</li><li>New Jersey</li><li>Nouvelle-Galles du Sud</li><li>Texas</li><li>Virginie</li><li>État de New York</li><li>Île-de-France</li></region><settlement><li>Calgary</li><li>Iowa City</li><li>Madrid</li><li>Paris</li><li>Rome</li><li>Sydney</li></settlement><orgName><li>Université de Calgary</li><li>Université de Sydney</li><li>Université de l'Iowa</li></orgName></list><tree><country name="États-Unis"><region name="Massachusetts"><name sortKey="Li, Jian Liang" sort="Li, Jian Liang" uniqKey="Li J" first="Jian-Liang" last="Li">Jian-Liang Li</name></region><name sortKey="Abramson, Ruth K" sort="Abramson, Ruth K" uniqKey="Abramson R" first="Ruth K" last="Abramson">Ruth K. Abramson</name><name sortKey="Ashizawa, Tetsuo" sort="Ashizawa, Tetsuo" uniqKey="Ashizawa T" first="Tetsuo" last="Ashizawa">Tetsuo Ashizawa</name><name sortKey="Cha, Jang Ho J" sort="Cha, Jang Ho J" uniqKey="Cha J" first="Jang-Ho J" last="Cha">Jang-Ho J. Cha</name><name sortKey="Conneally, P Michael" sort="Conneally, P Michael" uniqKey="Conneally P" first="P Michael" last="Conneally">P Michael Conneally</name><name sortKey="Cupples, L Adrienne" sort="Cupples, L Adrienne" uniqKey="Cupples L" first="L Adrienne" last="Cupples">L Adrienne Cupples</name><name sortKey="Djousse, Luc" sort="Djousse, Luc" uniqKey="Djousse L" first="Luc" last="Djoussé">Luc Djoussé</name><name sortKey="Duckett, Ayana" sort="Duckett, Ayana" uniqKey="Duckett A" first="Ayana" last="Duckett">Ayana Duckett</name><name sortKey="Gillis, Tammy" sort="Gillis, Tammy" uniqKey="Gillis T" first="Tammy" last="Gillis">Tammy Gillis</name><name sortKey="Gusella, James F" sort="Gusella, James F" uniqKey="Gusella J" first="James F" last="Gusella">James F. Gusella</name><name sortKey="Gusella, James F" sort="Gusella, James F" uniqKey="Gusella J" first="James F" last="Gusella">James F. Gusella</name><name sortKey="Hakky, Michael" sort="Hakky, Michael" uniqKey="Hakky M" first="Michael" last="Hakky">Michael Hakky</name><name sortKey="Harrison, Madaline B" sort="Harrison, Madaline B" uniqKey="Harrison M" first="Madaline B" last="Harrison">Madaline B. Harrison</name><name sortKey="Hersch, Steven M" sort="Hersch, Steven M" uniqKey="Hersch S" first="Steven M" last="Hersch">Steven M. Hersch</name><name sortKey="Jones, Randi" sort="Jones, Randi" uniqKey="Jones R" first="Randi" last="Jones">Randi Jones</name><name sortKey="Lazzarini, Alice" sort="Lazzarini, Alice" uniqKey="Lazzarini A" first="Alice" last="Lazzarini">Alice Lazzarini</name><name sortKey="Lazzarini, Alice" sort="Lazzarini, Alice" uniqKey="Lazzarini A" first="Alice" last="Lazzarini">Alice Lazzarini</name><name sortKey="Lechich, Anthony J" sort="Lechich, Anthony J" uniqKey="Lechich A" first="Anthony J" last="Lechich">Anthony J. Lechich</name><name sortKey="Li, Jian Liang" sort="Li, Jian Liang" uniqKey="Li J" first="Jian-Liang" last="Li">Jian-Liang Li</name><name sortKey="Li, Jian Liang" sort="Li, Jian Liang" uniqKey="Li J" first="Jian-Liang" last="Li">Jian-Liang Li</name><name sortKey="Macdonald, Marcy E" sort="Macdonald, Marcy E" uniqKey="Macdonald M" first="Marcy E" last="Macdonald">Marcy E. Macdonald</name><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name><name sortKey="Margolis, Russell L" sort="Margolis, Russell L" uniqKey="Margolis R" first="Russell L" last="Margolis">Russell L. Margolis</name><name sortKey="Margolis, Russell L" sort="Margolis, Russell L" uniqKey="Margolis R" first="Russell L" last="Margolis">Russell L. Margolis</name><name sortKey="Myers, Richard H" sort="Myers, Richard H" uniqKey="Myers R" first="Richard H" last="Myers">Richard H. Myers</name><name sortKey="Myers, Richard H" sort="Myers, Richard H" uniqKey="Myers R" first="Richard H" last="Myers">Richard H. Myers</name><name sortKey="Mysore, Jayalakshmi Srinidhi" sort="Mysore, Jayalakshmi Srinidhi" uniqKey="Mysore J" first="Jayalakshmi Srinidhi" last="Mysore">Jayalakshmi Srinidhi Mysore</name><name sortKey="Nance, Martha" sort="Nance, Martha" uniqKey="Nance M" first="Martha" last="Nance">Martha Nance</name><name sortKey="Paulsen, Jane S" sort="Paulsen, Jane S" uniqKey="Paulsen J" first="Jane S" last="Paulsen">Jane S. Paulsen</name><name sortKey="Penney, John B" sort="Penney, John B" uniqKey="Penney J" first="John B" last="Penney">John B. Penney</name><name sortKey="Perlman, Susan L" sort="Perlman, Susan L" uniqKey="Perlman S" first="Susan L" last="Perlman">Susan L. Perlman</name><name sortKey="Prakash, Ranjana" sort="Prakash, Ranjana" uniqKey="Prakash R" first="Ranjana" last="Prakash">Ranjana Prakash</name><name sortKey="Rosenblatt, Adam" sort="Rosenblatt, Adam" uniqKey="Rosenblatt A" first="Adam" last="Rosenblatt">Adam Rosenblatt</name><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A" last="Ross">Christopher A. Ross</name><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A" last="Ross">Christopher A. Ross</name><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A" last="Ross">Christopher A. Ross</name><name sortKey="Saint Hilaire, Marie H" sort="Saint Hilaire, Marie H" uniqKey="Saint Hilaire M" first="Marie H" last="Saint-Hilaire">Marie H. Saint-Hilaire</name><name sortKey="Wheeler, Vanessa C" sort="Wheeler, Vanessa C" uniqKey="Wheeler V" first="Vanessa C" last="Wheeler">Vanessa C. Wheeler</name><name sortKey="Xu, Gang" sort="Xu, Gang" uniqKey="Xu G" first="Gang" last="Xu">Gang Xu</name><name sortKey="Xu, Gang" sort="Xu, Gang" uniqKey="Xu G" first="Gang" last="Xu">Gang Xu</name><name sortKey="Zanko, Andrea" sort="Zanko, Andrea" uniqKey="Zanko A" first="Andrea" last="Zanko">Andrea Zanko</name></country><country name="Canada"><noRegion><name sortKey="Hayden, Michael R" sort="Hayden, Michael R" uniqKey="Hayden M" first="Michael R" last="Hayden">Michael R. Hayden</name></noRegion><name sortKey="Klimek, Mary Lou" sort="Klimek, Mary Lou" uniqKey="Klimek M" first="Mary Lou" last="Klimek">Mary Lou Klimek</name><name sortKey="Suchowersky, Oksana" sort="Suchowersky, Oksana" uniqKey="Suchowersky O" first="Oksana" last="Suchowersky">Oksana Suchowersky</name><name sortKey="Warby, Simon C" sort="Warby, Simon C" uniqKey="Warby S" first="Simon C" last="Warby">Simon C. Warby</name></country><country name="France"><region name="Île-de-France"><name sortKey="Durr, Alexandra" sort="Durr, Alexandra" uniqKey="Durr A" first="Alexandra" last="Durr">Alexandra Durr</name></region></country><country name="Royaume-Uni"><noRegion><name sortKey="Morrison, Patrick J" sort="Morrison, Patrick J" uniqKey="Morrison P" first="Patrick J" last="Morrison">Patrick J. Morrison</name></noRegion><name sortKey="Morrison, Patrick J" sort="Morrison, Patrick J" uniqKey="Morrison P" first="Patrick J" last="Morrison">Patrick J. Morrison</name></country><country name="Italie"><noRegion><name sortKey="Squitieri, Ferdinando" sort="Squitieri, Ferdinando" uniqKey="Squitieri F" first="Ferdinando" last="Squitieri">Ferdinando Squitieri</name></noRegion><name sortKey="Frati, Luigi" sort="Frati, Luigi" uniqKey="Frati L" first="Luigi" last="Frati">Luigi Frati</name><name sortKey="Frontali, Marina" sort="Frontali, Marina" uniqKey="Frontali M" first="Marina" last="Frontali">Marina Frontali</name><name sortKey="Novelletto, Andrea" sort="Novelletto, Andrea" uniqKey="Novelletto A" first="Andrea" last="Novelletto">Andrea Novelletto</name></country><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="G Mez Tortosa, Estrella" sort="G Mez Tortosa, Estrella" uniqKey="G Mez Tortosa E" first="Estrella" last="G Mez-Tortosa">Estrella G Mez-Tortosa</name></region><name sortKey="Garcia, Carmen Ayuso" sort="Garcia, Carmen Ayuso" uniqKey="Garcia C" first="Carmen Ayuso" last="García">Carmen Ayuso García</name></country><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Trent, Ronald Ja" sort="Trent, Ronald Ja" uniqKey="Trent R" first="Ronald Ja" last="Trent">Ronald Ja Trent</name></region><name sortKey="Mccusker, Elizabeth" sort="Mccusker, Elizabeth" uniqKey="Mccusker E" first="Elizabeth" last="Mccusker">Elizabeth Mccusker</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Main/Exploration
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Ou
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|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Main
|étape= Exploration
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|texte= Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
}}
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