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

MA van Es, JH Veldink, CGJ Saris, HM Blauw, PWJ Van Vught, A Birve, R Lemmens, HJ Schelhaas, EJN Groen, MHB Huisman, AJ van der Kooi, Martje Visser, C Dahlberg, Karol Estrada Gil, Fernando Rivadeneira, Bert Hofman, MJ Zwarts, PTC van Doormaal, D Rujescu, E StrengmanI Giegling, P Muglia, B Tomik, A Slowik, André Uitterlinden, C Hendrich, S Waibel, T Meyer, AC Ludolph, JD Glass, S Purcell, S Cichon, MM Nothen, HE Wichmann, S Schreiber, SHHM Vermeulen, LA Kiemeney, JHJ Wokke, S Cronin, RL McLaughlin, O Hardiman, K Fumoto, RJ Pasterkamp, V Meininger, J Melki, PN Leigh, CE Shaw, JE Landers, A Al-Chalabi, RH Brown, W Robberecht, PM Andersen, RA Ophoff, LH van den Berg

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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.
Original languageUndefined/Unknown
Pages (from-to)1083-U53
JournalNature Genetics
Volume41
Issue number10
DOIs
Publication statusPublished - 2009

Research programs

  • EMC MM-01-39-02
  • EMC NIHES-01-64-02

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