C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis

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Fältnamn	Indikatorer	Metadata
000		04482naa a2200721 4500
001		oai:DiVA.org:umu-92950
003		SwePub
008		140909s2014 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-929502 URI
024	7	a https://doi.org/10.1002/ana.241982 DOI
040		a (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Diekstra, Frank P.4 aut
245	1 0	a C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia :b A Genome-Wide Meta-Analysis
264		c 2014-06-27
264	1	b John Wiley & Sons,c 2014
338		a print2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Neurologi0 (SwePub)302072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Neurology0 (SwePub)302072 hsv//eng
700	1	a Van Deerlin, Vivianna M.4 aut
700	1	a van Swieten, John C.4 aut
700	1	a Al-Chalabi, Ammar4 aut
700	1	a Ludolph, Albert C.4 aut
700	1	a Weishaupt, Jochen H.4 aut
700	1	a Hardiman, Orla4 aut
700	1	a Landers, John E.4 aut
700	1	a Brown, Robert H., Jr.4 aut
700	1	a van Es, Michael A.4 aut
700	1	a Pasterkamp, R. Jeroen4 aut
700	1	a Koppers, Max4 aut
700	1	a Andersen, Peter M.u Umeå universitet,Klinisk neurovetenskap4 aut0 (Swepub:umu)pean0001
700	1	a Estrada, Karol4 aut
700	1	a Rivadeneira, Fernando4 aut
700	1	a Hofman, Albert4 aut
700	1	a Uitterlinden, Andre G.4 aut
700	1	a van Damme, Philip4 aut
700	1	a Melki, Judith4 aut
700	1	a Meininger, Vincent4 aut
700	1	a Shatunov, Aleksey4 aut
700	1	a Shaw, Christopher E.4 aut
700	1	a Leigh, P. Nigel4 aut
700	1	a Shaw, Pamela J.4 aut
700	1	a Morrison, Karen E.4 aut
700	1	a Fogh, Isabella4 aut
700	1	a Chio, Adriano4 aut
700	1	a Traynor, Bryan J.4 aut
700	1	a Czell, David4 aut
700	1	a Weber, Markus4 aut
700	1	a Heutink, Peter4 aut
700	1	a de Bakker, Paul I. W.4 aut
700	1	a Silani, Vincenzo4 aut
700	1	a Robberecht, Wim4 aut
700	1	a van den Berg, Leonard H.4 aut
700	1	a Veldink, Jan H.4 aut
710	2	a Umeå universitetb Klinisk neurovetenskap4 org
773	0	t Annals of Neurologyd : John Wiley & Sonsg 76:1, s. 120-133q 76:1<120-133x 0364-5134x 1531-8249
856	4	u https://europepmc.org/articles/pmc4137231?pdf=render
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-92950
856	4 8	u https://doi.org/10.1002/ana.24198

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