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

• Published in: Nature genetics Vol. 41; no. 10; pp. 1083 - 1087
• Main 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, Robberecht, Wim, Andersen, Peter M, Ophoff, Roel A, van den Berg, Leonard H
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2009; Nature Publishing Group
• Subjects: Agriculture; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain research; Cancer Research; Care and treatment; Cerebrospinal fluid. Meninges. Spinal cord; Charitable foundations; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 9; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia disorders; Disease Susceptibility; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genome-Wide Association Study; Health aspects; Human Genetics; Humans; Identification and classification; letter; Medical research; Medical sciences; Muscular dystrophy; Nervous system (semeiology, syndromes); Neurological disorders; Neurology; Polymorphism, Single Nucleotide; Quality control; Quantitative trait loci; Risk factors; Single nucleotide polymorphisms; Statistical analysis; Netherlands; Germany; Nervous system diseases; Sporadic; Central nervous system disease; Amyotrophic lateral sclerosis; Degenerative disease; Identification; Locus; Spinal cord disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.442

Leonard van den Berg, Roel Ophoff and colleagues present a genome-wide association study of sporadic amyotrophic lateral sclerosis. The work uncovers associated SNPs at 9p21.2 and an associated locus at 19p13.3 mapping to the UNC13A gene. 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 × 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 × 10 −9 . This SNP showed robust replication in the second cohort ( P = 1.86 × 10 −6 ), and a combined analysis over the two stages yielded P = 2.53 × 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 × 10 −9 , and rs3849942, with P = 1.01 × 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.