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- Title
Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.
- Authors
van Es, Michael A; Veldink, Jan H; Saris, Christiaan G J; Blauw, Hylke M; van Vught, Paul W J; Birve, Anna; Lemmens, Robin; Schelhaas, Helenius J; Groen, Ewout J N; Huisman, Mark H B; van der Kooi, Anneke J; de Visser, Marianne; Dahlberg, Caroline; Estrada, Karol; Rivadeneira, Fernando; Hofman, Albert; Zwarts, Machiel J; van Doormaal, Perry T C; Rujescu, Dan; Strengman, Eric; Giegling, Ina; Muglia, Pierandrea; Tomik, Barbara; Slowik, Agnieszka; Uitterlinden, Andre G; Hendrich, Corinna; Waibel, Stefan; Meyer, Thomas; Ludolph, Albert C; Glass, Jonathan D; Purcell, Shaun; Cichon, Sven; Nöthen, Markus M; Wichmann, H-Erich; Schreiber, Stefan; Vermeulen, Sita H H M; Kiemeney, Lambertus A; Wokke, John H J; Cronin, Simon; McLaughlin, Russell L; Hardiman, Orla; Fumoto, Katsumi; Pasterkamp, R Jeroen; Meininger, Vincent; Melki, Judith; Leigh, P Nigel; Shaw, Christopher E; Landers, John E; Al-Chalabi, Ammar; Brown, Robert H, Jr; Robberecht, Wim; Andersen, Peter M; Ophoff, Roel A; van den Berg, Leonard H
- Abstract
We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
- Publication
Nature genetics, 2009, Vol 41, Issue 10, p1083
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.442