Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

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Serval ID
serval:BIB_3F1A02E2DA61
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Production externe
Title
Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
Journal
Nature Genetics
Author(s)
van Rheenen W., Shatunov A., Dekker A.M., McLaughlin R.L., Diekstra F.P., Pulit S.L., van der Spek R.A., Võsa U., de Jong S., Robinson M.R., Yang J., Fogh I., van Doormaal P.T., Tazelaar G.H., Koppers M., Blokhuis A.M., Sproviero W., Jones A.R., Kenna K.P., van Eijk K.R., Harschnitz O., Schellevis R.D., Brands W.J., Medic J., Menelaou A., Vajda A., Ticozzi N., Lin K., Rogelj B., Vrabec K., Ravnik-Glavač M., Koritnik B., Zidar J., Leonardis L., Grošelj L.D., Millecamps S., Salachas F., Meininger V., de Carvalho M., Pinto S., Mora J.S., Rojas-García R., Polak M., Chandran S., Colville S., Swingler R., Morrison K.E., Shaw P.J., Hardy J., Orrell R.W., Pittman A., Sidle K., Fratta P., Malaspina A., Topp S., Petri S., Abdulla S., Drepper C., Sendtner M., Meyer T., Ophoff R.A., Staats K.A., Wiedau-Pazos M., Lomen-Hoerth C., Van Deerlin V.M., Trojanowski J.Q., Elman L., McCluskey L., Basak A.N., Tunca C., Hamzeiy H., Parman Y., Meitinger T., Lichtner P., Radivojkov-Blagojevic M., Andres C.R., Maurel C., Bensimon G., Landwehrmeyer B., Brice A., Payan C.A., Saker-Delye S., Dürr A., Wood N.W., Tittmann L., Lieb W., Franke A., Rietschel M., Cichon S., Nöthen M.M., Amouyel P., Tzourio C., Dartigues J.F., Uitterlinden A.G., Rivadeneira F., Estrada K., Hofman A., Curtis C., Blauw H.M., van der Kooi A.J., de Visser M., Goris A., Weber M., Shaw C.E., Smith B.N., Pansarasa O., Cereda C., Del Bo R., Comi G.P., D'Alfonso S., Bertolin C., Sorarù G., Mazzini L., Pensato V., Gellera C., Tiloca C., Ratti A., Calvo A., Moglia C., Brunetti M., Arcuti S., Capozzo R., Zecca C., Lunetta C., Penco S., Riva N., Padovani A., Filosto M., Muller B., Stuit R.J., Blair I., Zhang K., McCann E.P., Fifita J.A., Nicholson G.A., Rowe D.B., Pamphlett R., Kiernan M.C., Grosskreutz J., Witte O.W., Ringer T., Prell T., Stubendorff B., Kurth I., Hübner C.A., Leigh P.N., Casale F., Chio A., Beghi E., Pupillo E., Tortelli R., Logroscino G., Powell J., Ludolph A.C., Weishaupt J.H., Robberecht W., Van Damme P., Franke L., Pers T.H., Brown R.H., Glass J.D., Landers J.E., Hardiman O., Andersen P.M., Corcia P., Vourc'h P., Silani V., Wray N.R., Visscher P.M., de Bakker P.I., van Es M.A., Pasterkamp R.J., Lewis C.M., Breen G., Al-Chalabi A., van den Berg L.H., Veldink J.H.
Working group(s)
PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group
ISSN
1546-1718 (Electronic)
ISSN-L
1061-4036
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
48
Number
9
Pages
1043-1048
Language
english
Abstract
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Keywords
Amyotrophic Lateral Sclerosis/epidemiology, Amyotrophic Lateral Sclerosis/genetics, Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Munc18 Proteins/genetics, Mutation/genetics, Myelin Proteins/genetics, Netherlands/epidemiology, Proteins/genetics
DOI
10.1038/ng.3622
Pubmed
27455348
Web of science
000382398800015
Create date
06/12/2017 13:42
Last modification date
20/08/2019 14:36
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