The University of Southampton
University of Southampton Institutional Repository

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (?90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10?8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10?9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10?9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ?12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
2220-2231
Fogh, I.
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Ratti, A.
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Gellera, C.
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Lin, K.
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Tiloca, C.
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Moskvina, V.
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Corrado, L.
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Soraru, G.
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Cereda, C.
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Corti, S.
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Calini, D.
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Castellotti, B.
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Mazzini, L.
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Querin, G.
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Siciliano, G.
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Penco, S.
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Corbo, M.
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Sorbi, S.
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Filosto, M.
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Ferlini, A.
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Di Blasio, A.M.
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Signorini, S.
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Shatunov, A.
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Jones, A.
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Shaw, P.J.
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Morrison, K.E.
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Farmer, A.E.
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Van Damme, P.
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Robberecht, W.
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Chio, A.
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Traynor, B.J.
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Sendtner, M.
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Melki, J.
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Meininger, V.
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Hardiman, O.
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Leigh, N. P.
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Glass, J. D.
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Overste, D.
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Diekstra, F. P.
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Veldink, J. H.
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van Es, M. A.
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Shaw, C. E.
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Lewis, C. M.
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Landers, J. E.
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Ticozzi, N.
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D'Alfonso, S.
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van den Berg, L. H.
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Taroni, F.
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Powell, J.
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Silani, V.
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Filla, A.
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Massimo, F.
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Marsili, A.
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Viviana, P.
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Puorro, G.
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La Bella, V.
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Logroscino, G.
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Monsurro, M. R.
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Quattrone, A.
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Simone, I. L.
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Ahmeti, K. B.
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Ajroud-Driss, S.
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Armstrong, J.
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Birve, A.
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Blauw, H. M.
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Bruijn, L.
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Chen, W.
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Comeau, M. C.
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Cronin, S.
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Soraya, G. A.
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Groen, E. J.
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Heller, S.
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Huang, J.
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Hung, W.-Y.
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Khan, H.
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Jaworski, J. M.
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Langefeld, C. D.
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Marion, M. C.
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Miller, J. W.
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Mora, G.
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Rampersaud, E.
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Siddique, N.
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Siddique, T.
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Smith, B. N.
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Sufit, R.
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Topp, S.
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Vance, C.
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van Vught, P.
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Yang, Y.
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Zheng, J. G.
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Fogh, I.
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Ratti, A.
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Gellera, C.
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Lin, K.
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Tiloca, C.
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Moskvina, V.
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Soraru, G.
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Cereda, C.
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Corti, S.
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Gentilini, D.
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Calini, D.
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Castellotti, B.
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Mazzini, L.
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Querin, G.
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Gagliardi, S.
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Del Bo, R.
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Conforti, F.L.
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Siciliano, G.
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Inghilleri, M.
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Sacca, F.
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Bongioanni, P.
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Penco, S.
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Corbo, M.
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Sorbi, S.
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Filosto, M.
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Ferlini, A.
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Di Blasio, A.M.
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Signorini, S.
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Shatunov, A.
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Jones, A.
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Shaw, P.J.
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Farmer, A.E.
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Van Damme, P.
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Robberecht, W.
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Chio, A.
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Traynor, B.J.
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Sendtner, M.
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Melki, J.
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Meininger, V.
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Overste, D.
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Diekstra, F. P.
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Ticozzi, N.
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Pegoraro, E.
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Comi, G. P.
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D'Alfonso, S.
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van den Berg, L. H.
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Taroni, F.
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Silani, V.
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Brescia Morra, V.
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Filla, A.
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Massimo, F.
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Marsili, A.
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Viviana, P.
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Puorro, G.
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La Bella, V.
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Logroscino, G.
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Monsurro, M. R.
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Simone, I. L.
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Ahmeti, K. B.
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Ajroud-Driss, S.
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Armstrong, J.
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Birve, A.
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Blauw, H. M.
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Bruijn, L.
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Chen, W.
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Comeau, M. C.
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Cronin, S.
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Grab, J. D.
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Groen, E. J.
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Haines, J. L.
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Heller, S.
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Huang, J.
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Hung, W.-Y.
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Khan, H.
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Jaworski, J. M.
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Langefeld, C. D.
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Marion, M. C.
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McLaughlin, R. L.
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Miller, J. W.
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Mora, G.
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Pericak-Vance, M. A.
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Rampersaud, E.
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Siddique, N.
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Siddique, T.
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Smith, B. N.
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Sufit, R.
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Topp, S.
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Vance, C.
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van Vught, P.
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Yang, Y.
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Zheng, J. G.
a29175d2-72a1-4ada-bcb6-b715e0832a2e

Fogh, I., Ratti, A. and Gellera, C. et al. (2014) A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Human Molecular Genetics, 23 (8), 2220-2231. (doi:10.1093/hmg/ddt587). (PMID:24256812)

Record type: Article

Abstract

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (?90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10?8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10?9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10?9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ?12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

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Accepted/In Press date: 15 November 2013
Published date: 2014
Organisations: Medical Education

Identifiers

Local EPrints ID: 398325
URI: http://eprints.soton.ac.uk/id/eprint/398325
PURE UUID: 0d1cf89f-a11d-4123-a749-6e8377d54c97
ORCID for K.E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 21 Jul 2016 14:00
Last modified: 26 Nov 2019 01:32

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Contributors

Author: I. Fogh
Author: A. Ratti
Author: C. Gellera
Author: K. Lin
Author: C. Tiloca
Author: V. Moskvina
Author: L. Corrado
Author: G. Soraru
Author: C. Cereda
Author: S. Corti
Author: D. Gentilini
Author: D. Calini
Author: B. Castellotti
Author: L. Mazzini
Author: G. Querin
Author: S. Gagliardi
Author: R. Del Bo
Author: F.L. Conforti
Author: G. Siciliano
Author: M. Inghilleri
Author: F. Sacca
Author: P. Bongioanni
Author: S. Penco
Author: M. Corbo
Author: S. Sorbi
Author: M. Filosto
Author: A. Ferlini
Author: A.M. Di Blasio
Author: S. Signorini
Author: A. Shatunov
Author: A. Jones
Author: P.J. Shaw
Author: K.E. Morrison ORCID iD
Author: A.E. Farmer
Author: P. Van Damme
Author: W. Robberecht
Author: A. Chio
Author: B.J. Traynor
Author: M. Sendtner
Author: J. Melki
Author: V. Meininger
Author: O. Hardiman
Author: P. M. Andersen
Author: N. P. Leigh
Author: J. D. Glass
Author: D. Overste
Author: F. P. Diekstra
Author: J. H. Veldink
Author: M. A. van Es
Author: C. E. Shaw
Author: M. E. Weale
Author: C. M. Lewis
Author: J. Williams
Author: R. H. Brown
Author: J. E. Landers
Author: N. Ticozzi
Author: M. Ceroni
Author: E. Pegoraro
Author: G. P. Comi
Author: S. D'Alfonso
Author: L. H. van den Berg
Author: F. Taroni
Author: A. Al-Chalabi
Author: J. Powell
Author: V. Silani
Author: V. Brescia Morra
Author: A. Filla
Author: F. Massimo
Author: A. Marsili
Author: P. Viviana
Author: G. Puorro
Author: V. La Bella
Author: G. Logroscino
Author: M. R. Monsurro
Author: A. Quattrone
Author: I. L. Simone
Author: K. B. Ahmeti
Author: S. Ajroud-Driss
Author: J. Armstrong
Author: A. Birve
Author: H. M. Blauw
Author: L. Bruijn
Author: W. Chen
Author: M. C. Comeau
Author: S. Cronin
Author: G. A. Soraya
Author: J. D. Grab
Author: E. J. Groen
Author: J. L. Haines
Author: S. Heller
Author: J. Huang
Author: W.-Y. Hung
Author: H. Khan
Author: J. M. Jaworski
Author: C. D. Langefeld
Author: M. C. Marion
Author: R. L. McLaughlin
Author: J. W. Miller
Author: G. Mora
Author: M. A. Pericak-Vance
Author: E. Rampersaud
Author: N. Siddique
Author: T. Siddique
Author: B. N. Smith
Author: R. Sufit
Author: S. Topp
Author: C. Vance
Author: P. van Vught
Author: Y. Yang
Author: J. G. Zheng

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