Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.

Michael A van Es, Jan H Veldink, Christiaan G J Saris, Hylke M Blauw, Paul W J van Vught, Anna Birve, Robin Lemmens, Helenius J Schelhaas, Ewout J N Groen, Mark H B Huisman, Anneke J van der Kooi, Marianne de Visser, Caroline Dahlberg, Karol Estrada, Fernando Rivadeneira, Albert Hofman, Machiel J Zwarts, Perry T C van Doormaal, Dan Rujescu, Eric Strengman, Ina Giegling, Pierandrea Muglia, Barbara Tomik, Agnieszka Slowik, Andre G Uitterlinden, Corinna Hendrich, Stefan Waibel, Thomas Meyer, Albert C Ludolph, Jonathan D Glass, Shaun Purcell, Sven Cichon, Markus M Nöthen, H-Erich Wichmann, Stefan Schreiber, Sita H H M Vermeulen, Lambertus A Kiemeney, John H J Wokke, Simon Cronin, Russell L McLaughlin, Orla Hardiman, Katsumi Fumoto, R Jeroen Pasterkamp, Vincent Meininger, Judith Melki, P Nigel Leigh, Christopher E Shaw, John E Landers, Ammar Al-Chalabi, Robert H Brown, Wim Robberecht, Peter M Andersen, Roel A Ophoff, Leonard H van den Berg
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Nature genetics
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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.