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 × 104 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 × 109. This SNP showed robust replication in the second cohort (P = 1.86 × 106), and a combined analysis over the two stages yielded P = 2.53 × 1014. 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 × 109, and rs3849942, with P = 1.01 × 108) 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.

doi.org/10.1038/ng.442, hdl.handle.net/1765/24582
Nature Genetics
Erasmus MC: University Medical Center Rotterdam

van Es, M., Veldink, J., Saris, C., Blauw, H., van Vught, P., Birve, A., … van den Berg, L. (2009). Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature Genetics, 41(10), 1083–1087. doi:10.1038/ng.442