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 StrengmanIna 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. Noethen, 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*

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review

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 languageEnglish
Pages (from-to)1083-7
Number of pages6
JournalNature Genetics
Volume41
Issue number10
DOIs
Publication statusPublished - Oct 2009

Keywords

  • FRONTOTEMPORAL DEMENTIA
  • CONFERS SUSCEPTIBILITY
  • CHROMOSOME 9P
  • POPULATION
  • DISEASE
  • VARIANTS
  • RELEASE
  • LINKAGE
  • HAPMAP
  • DESIGN

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