A gene involved in neurotransmitter regulation is the latest addition to the handful of genetic loci linked to amyotrophic lateral sclerosis in genomewide association studies. In a Nature Genetics paper posted September 6, a bevy of ALS researchers led by Roel Ophoff and Leonard van den Berg of the University Medical Center in Utrecht, The Netherlands, report that a single nucleotide polymorphism near the gene UNC13A on chromosome 19 was linked with the disease in their multicenter study of 4,855 people with ALS and 14,953 control subjects. The researchers also found two SNPs on chromosome 9, near a locus previously associated with ALS. The new loci may prove to be useful clues to researchers trying to suss out the cause of sporadic ALS, which is by far the most common form of this disease. Joint first authors on the paper were Michael van Es and Jan Veldink, both from Utrecht.

Picking through the human genome in previous studies, researchers have linked ALS to loci near the genes ITPR2, FGGY, and DPP6 (see ARF related news story on Cronin et al., 2008 and van Es et al., 2008), although those associations are not significant in every study. With small sample sizes, false positives are a persistent worry. This team of researchers combined both previously published and new samples from several European countries and the United States for their analyses. They searched for ALS-related SNPs in an initial group of 2,323 people with ALS and 9,013 controls, then re-examined the most promising SNPs in a second group of 2,532 patients and 5,940 controls. It is the largest ALS GWAS to date, van Es told ARF in an e-mail.

DPP6 appeared to have some relationship with ALS in the first data set, but neither it nor ITPR2 or FGGY reached significance in the second cohort. ITPR2 and FGGY are probably not truly associated with ALS, van Es wrote; the results dovetail with another recent GWAS that also did not find a significant association between these loci and the disease (see ARF related news story on Chiò et al., 2009). As for DPP6, van Es wrote, it was nearly, but not quite, significant in the current study’s second cohort, and more work will be necessary to determine if its relationship to ALS is genuine.

The top hit in the second group was the chromosome 19 locus, an SNP squarely in the middle of the UNC13A gene. Since no other genes are close by, this variation in UNC13A is the best candidate for the ALS risk. Mechanistically, the association is appealing: UNC13A and related proteins regulate the release of neurotransmitters at the synapse, and in mice UNC13A deletions cause motor neuron defects (Varoqueaux et al., 2005). “It seems highly plausible that the gene plays a role in the pathogenesis,” van Es wrote.

Also overcoming the threshold to statistical significance were two SNPs on chromosome 9. They fall into the same range as SNPs previously associated with ALS combined with frontotemporal dementia (Morita et al., 2006; Vance et al., 2006; Valdmanis et al., 2007), suggesting the possibility that those studies may be pointing to the same, as-yet-undefined, gene. These new gene associations appear in the same issue of Nature Genetics that also publishes full reports of three new genes for Alzheimer disease gleaned from the largest GWAS to date for that disease (see ARF related ICAD story).—Amber Dance.

Reference:
van Es MA, Veldink JH, Saris CGJ, Blauw HM, van Vught PWJ, Birve A, Lemmens R, Schelhaas HJ, Groen EJN, Huisman MHB, van der Kooi AJ, de Visser M, Dahlberg C, Estrada K, Rivadeneira F, Hofman A, Zwarts MJ, van Doormaal PTC, Rujescu D, Strengman E, Giegling I, Muglia P, Tomik B, Slowik A, Uitterlinden AG, Hendrich C, Waibel S, Meyer T, Ludolph AC, Glass JD, Purcell S, Cichon S, Nöthen MM, Wichmann HE, Schreiber S, Vermeulen SHHM, Kiemeney LA, Wokke JHJ, Cronin S, McLaughlin RL, Hardiman O, Fumoto K, Pasterkamp RJ, Meininger V, Melki J, Leigh PN, Shaw CE, Landers JE, Al-Chalabi A, Brown RH Jr., Robberecht W, Andersen PM, Ophoff RA, van den Berg LH. Genomewide association study identifies c.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Gen. 2009 Sep 6. Abstract

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References

News Citations

  1. Sporadic ALS Linked to Potassium Channel
  2. Genomewide Screen for SNPs Linked to Sporadic ALS Finds…Nothing Yet
  3. Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits

Paper Citations

  1. . A genome-wide association study of sporadic ALS in a homogenous Irish population. Hum Mol Genet. 2008 Mar 1;17(5):768-74. PubMed.
  2. . Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2008 Jan;40(1):29-31. PubMed.
  3. . A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Apr 15;18(8):1524-32. PubMed.
  4. . Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol Cell Biol. 2005 Jul;25(14):5973-84. PubMed.
  5. . A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology. 2006 Mar 28;66(6):839-44. PubMed.
  6. . Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006 Apr;129(Pt 4):868-76. PubMed.
  7. . Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol. 2007 Feb;64(2):240-5. PubMed.
  8. . Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct;41(10):1083-7. PubMed.

Further Reading

Papers

  1. . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-11. PubMed.
  2. . Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27;323(5918):1205-8. PubMed.
  3. . Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med. 2007 Aug 23;357(8):775-88. PubMed.
  4. . Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct;41(10):1083-7. PubMed.
  5. . Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9004-9. PubMed.

News

  1. Motors and Muscles—Pacing ALS Progression
  2. New Gene for ALS: RNA Regulation May Be Common Culprit
  3. Sporadic ALS Linked to Potassium Channel
  4. Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
  5. Genomewide Screen for SNPs Linked to Sporadic ALS Finds…Nothing Yet

Primary Papers

  1. . Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct;41(10):1083-7. PubMed.