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C9orf72 and UNC13A ...
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Diekstra, Frank P.
(author)
C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia : A Genome-Wide Meta-Analysis
- Article/chapterEnglish2014
Publisher, publication year, extent ...
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2014-06-27
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John Wiley & Sons,2014
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:umu-92950
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-92950URI
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https://doi.org/10.1002/ana.24198DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Van Deerlin, Vivianna M.
(author)
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van Swieten, John C.
(author)
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Al-Chalabi, Ammar
(author)
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Ludolph, Albert C.
(author)
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Weishaupt, Jochen H.
(author)
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Hardiman, Orla
(author)
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Landers, John E.
(author)
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Brown, Robert H., Jr.
(author)
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van Es, Michael A.
(author)
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Pasterkamp, R. Jeroen
(author)
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Koppers, Max
(author)
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Andersen, Peter M.Umeå universitet,Klinisk neurovetenskap(Swepub:umu)pean0001
(author)
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Estrada, Karol
(author)
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Rivadeneira, Fernando
(author)
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Hofman, Albert
(author)
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Uitterlinden, Andre G.
(author)
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van Damme, Philip
(author)
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Melki, Judith
(author)
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Meininger, Vincent
(author)
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Shatunov, Aleksey
(author)
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Shaw, Christopher E.
(author)
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Leigh, P. Nigel
(author)
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Shaw, Pamela J.
(author)
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Morrison, Karen E.
(author)
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Fogh, Isabella
(author)
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Chio, Adriano
(author)
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Traynor, Bryan J.
(author)
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Czell, David
(author)
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Weber, Markus
(author)
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Heutink, Peter
(author)
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de Bakker, Paul I. W.
(author)
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Silani, Vincenzo
(author)
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Robberecht, Wim
(author)
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van den Berg, Leonard H.
(author)
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Veldink, Jan H.
(author)
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Umeå universitetKlinisk neurovetenskap
(creator_code:org_t)
Related titles
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In:Annals of Neurology: John Wiley & Sons76:1, s. 120-1330364-51341531-8249
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Diekstra, Frank ...
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Van Deerlin, Viv ...
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van Swieten, Joh ...
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Al-Chalabi, Amma ...
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Ludolph, Albert ...
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Weishaupt, Joche ...
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Hardiman, Orla
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Landers, John E.
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Brown, Robert H. ...
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van Es, Michael ...
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Pasterkamp, R. J ...
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Koppers, Max
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Andersen, Peter ...
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Estrada, Karol
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Rivadeneira, Fer ...
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Hofman, Albert
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Uitterlinden, An ...
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van Damme, Phili ...
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Melki, Judith
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Meininger, Vince ...
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Shatunov, Alekse ...
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Shaw, Christophe ...
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Leigh, P. Nigel
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Shaw, Pamela J.
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Morrison, Karen ...
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Fogh, Isabella
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Chio, Adriano
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Traynor, Bryan J ...
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Czell, David
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Weber, Markus
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Heutink, Peter
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de Bakker, Paul ...
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Silani, Vincenzo
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Robberecht, Wim
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van den Berg, Le ...
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Veldink, Jan H.
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and Neurology
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